Treatment of colds and cough with a combination of a cyclooxygenase-2 selective inhibitor and a colds and cough active ingredient and compositions thereof

ABSTRACT

A method for the treatment, prevention and amelioration of colds and/or cough in a subject in need of such treatment, prevention and amelioration, comprises administering to the subject a cyclooxygenase-2 selective inhibitor or prodrug thereof and one or more colds and cough active ingredient. Compositions, pharmaceutical compositions and kits for practicing the method are also disclosed.

CROSS-REFERENCE TO RELATED PATENTS AND PATENT APPLICATIONS

[0001] The subject matter of the present invention is related to andclaims the benefit of co-pending and commonly assigned U.S. ProvisionalPatent Application Serial No. 60/354,135, filed on Feb. 4, 2002, whichapplication is hereby incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] (1) Field of the Invention

[0003] The present invention relates to the treatment of colds andcoughs, and more particularly to the treatment of colds and coughs byadministering to a subject a combination of a cyclooxygenase-2 selectiveinhibitor and a colds and cough active ingredient.

[0004] (2) Description of the Related Art

[0005] The common cold is an acute viral infection of the mucousmembranes of the nose and throat, often involving the sinuses. Thetypical sore throat, sneezing, and fatigue can be accompanied by bodyaches, headache, low fever, and chills. The congested and dischargingmucous membrane may become a fertile ground for s secondary bacterialinfection that can spread to the larynx, bronchi, lungs, or ears.Uncomplicated infections usually last from three to ten days.

[0006] Colds are caused by any one of up to 200 viruses—such as therhinoviruses, coronaviruses, or respiratory syncytial virus. Infectionwith a viral strain confers only a temporary immunity to that strain.Colds in infants and young children caused by the respiratory syncytialvirus can progress to pneumonia and other complications, and can resultin death.

[0007] It is believed that there is no treatment for the common coldother than that aimed at relieving symptoms and keeping the body wellrested, fed, and hydrated. However, many compounds have been found thatare effective in the relief of aches and pain (analgesics—usuallynon-steroidal anti-inflammatory drugs, or NSAID's), in reducing sneezingand runny nose (antihistamines), for the suppression of coughs(antitussives), for the breakup of nasal and sinus congestion(decongestants), and for helping clear the lungs of excess mucus(expectorants). Many of these medications are available commercially,and more are now being developed.

[0008] One promising area for colds medications is the development ofnew antiviral agents. Older antiviral compounds such as aciclovir haveproven to be effective against herpesviruses, and new materials such asdipyridamole, impulsin, and pleconaril have shown promise for theprevention and/or amelioration of colds. See, e.g., Jefferson, T. O. etal., Cochrane Database Syst. Rev., 1:3 CD002743 (2001); and Romero, J.R., Expert. Opin. Investig. Drugs, 10(2):369-379 (2001).

[0009] Recently, significant progress has also been made in the field ofinflammation, and the development of drugs that show promise for thetreatment of the inflammation-related disorders of osteoarthritis andrheumatoid arthritis. It has been known for some time that many of thecommon non-steroidal antiinflammatory drugs (NSAIDs) modulateprostagiandin synthesis by inhibition of cyclooxygenases that catalyzethe transformation of arachidonic acid—the first step in theprostaglandin synthesis pathway. However, the use of high doses of manycommon NSAIDs can produce severe side effects that limit theirtherapeutic potential.

[0010] In an effort to reduce the unwanted side effects of commonNSAIDS, it was discovered that two cyclooxygenases are involved in thetransformation of arachidonic acid as the first step in theprostaglandin synthesis pathway. These enzymes have been termedcyclooxygenase-1 (Cox-1) and cyclooxygenase-2 (Cox-2). See, Needleman,P. et al., J. Rheumatol., 24, Suppl.49:6-8 (1997). See, Fu, J. Y., etal., J. Biol. Chem., 265(28):16737-40 (1990).

[0011] Cox-1 has been shown to be a constitutively produced enzyme thatis involved in many of the non-inflammatory regulatory functionsassociated with prostaglandins. Cox-2, on the other hand, is aninducible enzyme having significant involvement in the inflammatoryprocess. Inflammation causes the induction of Cox-2, leading to therelease of prostanoids, which sensitize peripheral nociceptor terminalsand produce localized pain hypersensitivity. See, e.g., Samad, T. A. etal., Nature, 410(6827):471-5 (2001). Many of the common NSAIDs are nowknown to be inhibitors of both Cox-1 and Cox-2. Accordingly, whenadministered in sufficiently high levels, these NSAIDs affect not onlythe inflammatory consequences of Cox-2 activity, but also the beneficialactivities of Cox-1.

[0012] Recently, compounds that selectively inhibit Cox-2 to a greaterextent than the activity of Cox-1 have been discovered. The newCox-2-selective inhibitors are believed to offer advantages that includethe capacity to prevent or reduce inflammation while avoiding harmfulside effects associated with the inhibition of Cox-1.

[0013] Interestingly, for purposes of the present invention, it has beenreported that isolated alkali metal and alkali-earth metal salts ofacetaminophen could be used for treatment of mammals in need of ananalgesic or antipyretic agent. U.S. Pat. No. 6,160,020 to Ohannesian etal. However, the purpose of the invention was to provide metal salts ofacetaminophen with improved aqueous solubility and taste. Theacetaminophen salts could be combined with other active ingredients suchas analgesics, decongestants, expectorants, antitussives,antihistamines, diuretics, gastrointestinal agents, bronchodilators, andsleep-inducing agents. The analgesic could be supplied byacetylsalicylic acid (aspirin), indomethacin, and Cox-2 inhibitors suchas flosulide, nimesulide, celecoxib, 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole, meloxicam,nambumethone, and etodolac, among other compounds. However, noindication was provided that the analgesic should be a Cox-2 selectiveinhibitor. Furthermore, the additional chemical reactions andseparations necessary to provide isolated metal salts of acetaminophen,rather than the acid form of acetaminophen, result in additional expenseand require more complex production techniques.

[0014] U.S. Pat. Nos. 6,271,253; 6,034,256; 6,077,850; and 6,271,253 toCarter et al. describe the use of certain substituted benzopyran Cox-2inhibitors for the treatment of inflammation. It is also stated that thesubstituted benzopyran Cox-2 inhibitors can be used in addition to otheranti-inflammatories, and in combination with opioids and otheranalgesics, codeine, hydrocodone, antihistamines, decongestants,diuretics and antitussive agents.

[0015] U.S. Pat. No. 6,303,628 to Nakao et al. describes certainbicycliccarbonyl indole compounds as having Cox-2 selective inhibitoryactivity, and states that these compounds are useful for treating Cox-2mediated diseases—including co-administration with such otheringredients as another pain reliever, a potentiator, a decongestant, anantitussive, a prostaglandin, a diuretic, an antihistamine, anticanceragents, and the like.

[0016] From the foregoing, it can be seen that a need exists forimproved treatment methods and compositions for colds and coughs. Itwould also be useful if such improved methods and compositions could beprovided that combined the effectiveness of Cox-2 selective inhibitorswith the effectiveness of one or more compounds that are useful forameliorating the symptoms of colds and/or cough. Moreover, it would beuseful if such methods and compositions avoided the requirement forspecial forms of active ingredients, in particular, if they could befree of such materials as isolated metal salts of an activeingredient—isolated metal salts of acetaminophen as an example.

SUMMARY OF THE INVENTION

[0017] Briefly, therefore the present invention is directed to a novelmethod for the treatment, prevention and amelioration of colds and/orcough in a subject in need of such treatment, prevention andamelioration, the method comprising administering to the subject acyclooxygenase-2 selective inhibitor or prodrug thereof and one or morecolds and cough active ingredient.

[0018] The present invention is also directed to a novel composition forthe treatment, prevention and amelioration of colds and/or cough in asubject in need of such treatment, prevention and amelioration, thecomposition comprising a cyclooxygenase-2 selective inhibitor and acolds and cough active ingredient.

[0019] The present invention is also directed to a novel composition forthe treatment, prevention and amelioration of colds and/or cough in asubject in need of such treatment, prevention and amelioration, thecomposition comprising a cyclooxygenase-2 selective inhibitor selectedfrom the group consisting of celecoxib, parecoxib and valdecoxib, and acolds and cough active ingredient selected from the group consisting ofchlorpheniramine, cetirzine, loratadine, codeine, hydrocodone,carbetapentane, dextromethorphan, aspirin, guaifenesin, ephedrine,ephinephrine, phenylephrine, phenylpropanolamine, pseudoephedrine,impulsin, pleconaril, aciclovir, and ganciclovir.

[0020] The present invention is also directed to a novel composition forthe treatment, prevention and amelioration of colds and/or cough in asubject in need of such treatment, prevention and amelioration, thecomposition comprising a cyclooxygenase-2 selective inhibitor and acombination of two or more colds and cough active ingredients.

[0021] The present invention is also directed to a novel pharmaceuticalcomposition for the treatment, prevention and amelioration of coldsand/or cough in a subject in need of such treatment, prevention andamelioration, the composition comprising a cyclooxygenase-2 selectiveinhibitor, a colds and cough active ingredient, and apharmaceutically-acceptable excipient.

[0022] The present invention is also directed to a novel kit that issuitable for use in the treatment, prevention or amelioration of coldsand/or cough, the kit comprises a first dosage form comprising a coldsand cough active ingredient and a second dosage form comprising acyclooxygenase-2 selective inhibitor or prodrug thereof, in quantitieswhich comprise a therapeutically effective amount of the combination ofthe compounds for the treatment, prevention, or amelioration of coldsand/or cough.

[0023] Among the several advantages found to be achieved by the presentinvention, therefore, may be noted the provision of improved treatmentmethods and compositions for colds and coughs, the provision of suchimproved methods and compositions that combined the effectiveness ofCox-2 selective inhibitors with the effectiveness of one or morecompounds that are useful for ameliorating the symptoms of colds and/orcough, the provision of such methods and compositions that avoided therequirement for special forms of active ingredients, the provision ofsuch methods and compositions that were free of such materials asisolated metal salts of an active ingredient, and in particular,isolated metal salts of acetaminophen.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In accordance with the present invention, it has been discoveredthat some or all of the symptoms of colds and cough can be treated,prevented or ameliorated in a subject in need of such treatment,prevention or amelioration by administering to the subject acyclooxygenase-2 selective inhibitor or prodrug thereof and one or morecolds and cough active ingredient. In order to reduce the costs andcomplications of producing the novel combinations, it has been foundthat combinations comprising acetaminophen are not required to containthe isolated metal salt of acetaminophen. Indeed, in combinationscomprising analgesics, it has been found that it is not required thatthe analgesic be an isolated metal salt of the analgesic.

[0025] In certain embodiments, the compositions of the inventioncomprise one or more Cox-2 selective inhibitors in combination with twoor more colds and cough active ingredients.

[0026] In each of the embodiments of the subject methods andcompositions, it has been found that the anti-inflammatory and analgesiceffects of a Cox-2 selective inhibitor can be enjoyed without theadverse side effects of some other common NSAIDs. Moreover, the novelmethods and compositions provide the benefits of the colds and coughactive ingredients that are included.

[0027] One component of the combination of the present invention is acycloxygenase-2 selective inhibitor. The terms “cyclooxygenase-2selective inhibitor”, or “Cox-2 selective inhibitor”, which can be usedinterchangeably herein, embrace compounds which selectively inhibitcyclooxygenase-2 over cyclooxygenase-1, and also includepharmaceutically acceptable salts of those compounds.

[0028] In practice, the selectivity of a Cox-2 inhibitor variesdepending upon the condition under which the test is performed and onthe inhibitors being tested. However, for the purposes of thisspecification, the selectivity of a Cox-2 inhibitor can be measured as aratio of the in vitro or in vivo IC₅₀ value for inhibition of Cox-1,divided by the IC₅₀ value for inhibition of Cox-2 (Cox-1 IC₅₀/Cox-2IC₅₀). A Cox-2 selective inhibitor is any inhibitor for which the ratioof Cox-1 IC₅₀ to Cox-2 IC₅₀ is greater than 1. In preferred embodiments,this ratio is greater than 2, more preferably greater than 5, yet morepreferably greater than 10, still more preferably greater than 50, andmore preferably still greater than 100.

[0029] As used herein, the term “IC₅₀” refers to the concentration of acompound that is required to produce 50% inhibition of cyclooxygenaseactivity. Preferred cyclooxygenase-2 selective inhibitors of the presentinvention have a cyclooxygenase-2 IC₅₀ of less than about 1 μM, morepreferred of less than about 0.5 μM, and even more preferred of lessthan about 0.2 μM.

[0030] Preferred cycloxoygenase-2 selective inhibitors have acyclooxygenase-1 IC₅₀ of greater than about 1 μM, and more preferably ofgreater than 20 μM. Such preferred selectivity may indicate an abilityto reduce the incidence of common NSAID-induced side effects.

[0031] Also included within the scope of the present invention arecompounds that act as prodrugs of cyclooxygenase-2-selective inhibitors.As used herein in reference to Cox-2 selective inhibitors, the term“prodrug” refers to a chemical compound that can be converted into anactive Cox-2 selective inhibitor by metabolic or simple chemicalprocesses within the body of the subject. One example of a prodrug for aCox-2 selective inhibitor is parecoxib, which is a therapeuticallyeffective prodrug of the tricyclic cyclooxygenase-2 selective inhibitorvaldecoxib. An example of a preferred Cox-2 selective inhibitor prodrugis parecoxib sodium. A class of prodrugs of Cox-2 inhibitors isdescribed in U.S. Pat. No. 5,932,598.

[0032] The cyclooxygenase-2 selective inhibitor of the present inventioncan be, for example, the Cox-2 selective inhibitor meloxicam, FormulaB-1 (CAS registry number 71125-38-7), or a pharmaceutically acceptablesalt or prodrug thereof.

[0033] In another embodiment of the invention the cyclooxygenase-2selective inhibitor can be the Cox-2 selective inhibitor RS 57067,6-[[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]methyl]-3(2H)-pyridazinone,Formula B-2 (CAS registry number 179382-91-3), or a pharmaceuticallyacceptable salt or prodrug thereof.

[0034] In a another embodiment of the invention the cyclooxygenase-2selective inhibitor is of the chromene/chroman structural class that isa substituted benzopyran or a substituted benzopyran analog, and evenmore preferably selected from the group consisting of substitutedbenzothiopyrans, dihydroquinolines, or dihydronaphthalenes having thestructure of any one of the compounds having a structure shown bygeneral Formulas I, II, III, IV, V, and VI, shown below, and possessing,by way of example and not limitation, the structures disclosed in Table1, including the diastereomers, enantiomers, racemates, tautomers,salts, esters, amides and prodrugs thereof.

[0035] Benzopyrans that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include substituted benzopyranderivatives that are described in U.S. Pat. No. 6,271,253. One suchclass of compounds is defined by the general formula shown below informulas I:

[0036] wherein X¹ is selected from O, S, CR^(c) R^(b) and NR^(a);

[0037] wherein R^(a) is selected from hydrido, C₁-C₃-alkyl, (optionallysubstituted phenyl)-C₁-C₃-alkyl, acyl and carboxy-C₁-C₆-alkyl;

[0038] wherein each of R^(b) and R^(c) is independently selected fromhydrido, C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl; orwherein CR^(b) R^(c) forms a 3-6 membered cycloalkyl ring;

[0039] wherein R¹ is selected from carboxyl, aminocarbonyl,C₁-C₆-alkylsulfonylaminocarbonyl and C₁-C₆-alkoxycarbonyl;

[0040] wherein R² is selected from hydrido, phenyl, thienyl, C₁-C₆-alkyland C₂-C₆-alkenyl;

[0041] wherein R³ is selected from C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl;

[0042] wherein R⁴ is one or more radicals independently selected fromhydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,halo-C₂-C₆-alkynyl, aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl,aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, methylenedioxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkyloxy,heteroaryl-C₁-C₆-alkyloxy, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio,C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,C₁-C₃-(haloalkyl-₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-C₁-C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁-C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₆-alkylaminosulfonyl, heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₁-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and

[0043] wherein the A ring atoms A¹, A², A³ and A⁴ are independentlyselected from carbon and nitrogen with the proviso that at least two ofA¹, A², A³ and A⁴ are carbon;

[0044] or wherein R⁴ together with ring A forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl anddibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.

[0045] Another class of benzopyran derivatives that can serve as theCox-2 selective inhibitor of the present invention includes a compoundhaving the structure of formula II:

[0046] wherein X² is selected from O, S, CR^(c) R^(b) and NR^(a);

[0047] wherein R^(a) is selected from hydrido, C₁-C₃-alkyl, (optionallysubstituted phenyl)-C₁-C₃-alkyl, alkylsulfonyl, phenylsulfonyl,benzylsulfonyl, acyl and carboxy-C₁-C₆-alkyl;

[0048] wherein each of R^(b) and R^(c) is independently selected fromhydrido, C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl; orwherein CR^(c) R^(b) form a cyclopropyl ring;

[0049] wherein R⁵ is selected from carboxyl, aminocarbonyl,C₁-C₆-alkylsulfonylaminocarbonyl and C₁-C₆-alkoxycarbonyl;

[0050] wherein R⁶ is selected from hydrido, phenyl, thienyl,C₂-C₆-alkynyl and C₂-C₆-alkenyl;

[0051] wherein R⁷ is selected from C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl;wherein R⁸ is one or more radicals independently selected from hydrido,halo, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl,aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl, aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy,methylenedioxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, —O(CF₂)₂O—,aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkyloxy,heteroaryl-C₁-C₆-alkyloxy, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio,C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,C₁-C₃-(haloalkyl-C₁-C₃-hydroxyalkyl), C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-C₁-C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁-C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₆-alkylaminosulfonyl, heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and

[0052] wherein the D ring atoms D¹, D², D³ and D⁴ are independentlyselected from carbon and nitrogen with the proviso that at least two ofD¹, D², D³ and D⁴ are carbon; or

[0053] wherein R⁸ together with ring D forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl anddibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.

[0054] Other benzopyran Cox-2 selective inhibitors useful in thepractice of the present invention are described in U.S. Pat. Nos.6,034,256 and 6,077,850. The general formula for these compounds isshown in formula III:

[0055] Formula III is:

[0056] wherein X³ is selected from the group consisting of O or S orNR^(a);

[0057] wherein R^(a) is alkyl;

[0058] wherein R⁹ is selected from the group consisting of H and aryl;

[0059] wherein R¹⁰ is selected from the group consisting of carboxyl,aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;

[0060] wherein R¹¹ is selected from the group consisting of haloalkyl,alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one ormore radicals selected from alkylthio, nitro and alkylsulfonyl; and

[0061] wherein R¹² is selected from the group consisting of one or moreradicals selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy,alkylamino, arylamino, aralkylamino, heteroarylamino,heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl,heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl,hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionallysubstituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl,arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or

[0062] wherein R¹² together with ring E forms a naphthyl radical; or anisomer or pharmaceutically acceptable salt thereof; and including thediastereomers, enantiomers, racemates, tautomers, salts, esters, amidesand prodrugs thereof.

[0063] A related class of compounds useful as cyclooxygenase-2 selectiveinhibitors in the present invention is described by Formulas IV and V:

[0064] wherein X⁴ is selected from O or S or NR^(a);

[0065] wherein R^(a) is alkyl;

[0066] wherein R¹³ is selected from carboxyl, aminocarbonyl,alkylsulfonylaminocarbonyl and alkoxycarbonyl;

[0067] wherein R¹⁴ is selected from haloalkyl, alkyl, aralkyl,cycloalkyl and aryl optionally substituted with one or more radicalsselected from alkylthio, nitro and alkylsulfonyl; and

[0068] wherein R¹⁵ is one or more radicals selected from hydrido, halo,alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino,aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino,aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl,heteroarylaminosulfonyl, aralkylaminosulfonyl,heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, andalkylcarbonyl;

[0069] or wherein R¹⁵ together with ring G forms a naphthyl radical; oran isomer or pharmaceutically acceptable salt thereof.

[0070] Formula V is:

[0071] wherein:

[0072] X⁵ is selected from the group consisting of O or S or NR^(b);

[0073] R^(b) is alkyl;

[0074] R¹⁶ is selected from the group consisting of carboxyl,aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;

[0075] R¹⁷ is selected from the group consisting of haloalkyl, alkyl,aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl,cycloalkyl, and aryl each is independently optionally substituted withone or more radicals selected from the group consisting of alkylthio,nitro and alkylsulfonyl; and

[0076] R¹⁸ is one or more radicals selected from the group consisting ofhydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy,aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino,arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro,amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl,heteroarylaminosulfonyl, aralkylaminosulfonyl,heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, andalkylcarbonyl; or wherein R¹⁸ together with ring A forms a naphthylradical;

[0077] or an isomer or pharmaceutically acceptable salt thereof.

[0078] The cyclooxygenase-2 selective inhibitor may also be a compoundof Formula V, wherein:

[0079] X⁵ is selected from the group consisting of oxygen and sulfur;

[0080] R¹⁶ is selected from the group consisting of carboxyl, loweralkyl, lower aralkyl and lower alkoxycarbonyl;

[0081] R¹⁷ is selected from the group consisting of lower haloalkyl,lower cycloalkyl and phenyl; and

[0082] R¹⁸ is one or more radicals selected from the group of consistingof hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lowerhaloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, loweralkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-memberedheteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-memberednitrogen-containing heterocyclosulfonyl, 6-membered-nitrogen containingheterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl,lower aralkylcarbonyl, and lower alkylcarbonyl; or

[0083] wherein R¹⁸ together with ring A forms a naphthyl radical; or anisomer or pharmaceutically acceptable salt thereof.

[0084] The cyclooxygenase-2 selective inhibitor may also be a compoundof Formula V, wherein:

[0085] X⁵ is selected from the group consisting of oxygen and sulfur;

[0086] R¹⁶ is carboxyl; R¹⁷ is lower haloalkyl; and

[0087] R¹⁸ is one or more radicals selected from the group consisting ofhydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, loweralkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-memberedheteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl,lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-memberednitrogen-containing heterocyclosulfonyl, optionally substituted phenyl,lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R¹⁸ togetherwith ring A forms a naphthyl radical;

[0088] or an isomer or pharmaceutically acceptable salt thereof.

[0089] The cyclooxygenase-2 selective inhibitor may also be a compoundof Formula V, wherein:

[0090] X⁵ is selected from the group consisting of oxygen and sulfur;

[0091] R¹⁶ is selected from the group consisting of carboxyl, loweralkyl, lower aralkyl and lower alkoxycarbonyl;

[0092] R¹⁷ is selected from the group consisting of fluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, d ifluoroethyl, d ifluoropropyl, dichloroethyl,dichloropropyl, difluoromethyl, and trifluoromethyl; and

[0093] R¹⁸ is one or more radicals selected from the group consisting ofhydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl,tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy,isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl,trifluoromethoxy, amino, N,N-dimethylamino, N,N-diethylamino,N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl,N-(2-furylmethyl)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl,aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl,2,2-dimethylethylaminosulfonyl, N,N-dimethylaminosulfonyl,N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl,benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or

[0094] wherein R² together with ring A forms a naphthyl radical;

[0095] or an isomer or pharmaceutically acceptable salt thereof.

[0096] The cyclooxygenase-2 selective inhibitor may also be a compoundof Formula V, wherein:

[0097] X⁵ is selected from the group consisting of oxygen and sulfur;

[0098] R¹⁶ is selected from the group consisting of carboxyl, loweralkyl, lower aralkyl and lower alkoxycarbonyl;

[0099] R¹⁷ is selected from the group consisting trifluoromethyl andpentafluoroethyl; and

[0100] R¹⁸ is one or more radicals selected from the group consisting ofhydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl,tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy,N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl,N-(2-furylmethyl)aminosulfonyl, N,N-dimethylaminosulfonyl,N-methylaminosulfonyl, N-(2,2-dimethylethyl)aminosulfonyl,dimethylaminosulfonyl, 2-methylpropylaminosulfonyl,N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; orwherein R¹⁸ together with ring A forms a naphthyl radical;

[0101] or an isomer or prodrug thereof.

[0102] The cyclooxygenase-2 selective inhibitor of the present inventioncan also be a compound having the structure of Formula VI:

[0103] wherein:

[0104] X⁶ is selected from the group consisting of O and S;

[0105] R¹⁹ is lower haloalkyl;

[0106] R²⁰ is selected from the group consisting of hydrido, and halo;

[0107] R²¹ is selected from the group consisting of hydrido, halo, loweralkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lowerdialkylaminosulfonyl, lower alkylaminosulfonyl, loweraralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-memberednitrogen-containing heterocyclosulfonyl, and 6-memberednitrogen-containing heterocyclosulfonyl;

[0108] R²² is selected from the group consisting of hydrido, loweralkyl, halo, lower alkoxy, and aryl; and

[0109] R²³ is selected from the group consisting of the group consistingof hydrido, halo, lower alkyl, lower alkoxy, and aryl;

[0110] or an isomer or prodrug thereof.

[0111] The cyclooxygenase-2 selective inhibitor can also be a compoundof having the structure of Formula VI, wherein:

[0112] X⁶ is selected from the group consisting of O and S;

[0113] R¹⁹ is selected from the group consisting of trifluoromethyl andpentafluoroethyl;

[0114] R²⁰ is selected from the group consisting of hydrido, chloro, andfluoro;

[0115] R²¹ is selected from the group consisting of hydrido, chloro,bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy,benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl,methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl,methylpropylaminosulfonyl, methylsulfonyl, and morpholinosulfonyl;

[0116] R²² is selected from the group consisting of hydrido, methyl,ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl;and

[0117] R²³ is selected from the group consisting of hydrido, chloro,bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl;

[0118] or an isomer or prodrug thereof. TABLE 1 Examples of ChromeneCox-2 Selective Inhibitors Compound Number Structural Formula B-3

6-Nitro-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid B-4

6-Chloro-8-methyl-2-trifluoromethyl- 2H-1-benzopyran-3-Carboxylic acidB-5

((S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl-2H-1-benzopyran-3-Carboxylic acid B-6

2-Trifluoromethyl-2H-naphtho[2,3-b]pyran- 3-carboxylic acid B-7

6-Chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid B-8

((S)-6,8-Dichloro-2-(trifluoromethyl)- 2H-1-benzopyran-3-carboxylic acidB-9

6-Chloro-2-(trifluoromethyl)-4-phenyl-2H- 1-benzopyran-3-carboxylic acidB-10

6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)- 2H-1-benzopyran-3-carboxylicacid B-11

2-(Trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylic acid B-12

6,8-Dichloro-2-trifluoromethyl-2H-1- benzothiopyran-3-carboxylic acidB-13

6-(1,1-Dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid B-14

6,7-Difluoro-1,2-dihydro-2-(trifluoromethyl)- 3-quinolinecarboxylic acidB-15

6-Chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)- 3-quinolinecarboxylicacid B-16

6-Chloro-2-(trifluoromethyl)-1,2- dihydro[1,8]naphthyridine-3-carboxylicacid B-17

((S)-6-Chloro-1,2-dihydro-2-(trifluoromethyl)- 3-quinolinecarboxylicacid

[0119] Examples of specific compounds that are useful for thecyclooxygenase-2 selective inhibitor include (without limitation):

[0120] a1)8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo(1,2-a)pyridine;

[0121] a2) 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone;

[0122] a3)5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole;

[0123] a4)4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole;

[0124] a5)4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide

[0125] a6)4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;

[0126] a7)4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;

[0127] a8)4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;

[0128] a9)4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;

[0129] a10)4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide;

[0130] b1)4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzenesulfonamide;

[0131] b2) 4-(4-chloro-3,5-d diphenyl-1H-pyrazol-1-yl)benzenesulfonamide

[0132] b3)4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0133] b4)4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0134] b5)4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0135] b6)4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0136] b7)4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0137] b8)4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0138] b9)4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0139] b10)4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0140] c1)4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

[0141] c2)4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0142] c3)4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0143] c4)4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0144] c5)4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0145] c6) 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

[0146] c7)4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0147] c8)4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0148] c9)5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;

[0149] c10)4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;

[0150] d1)6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene;

[0151] d2)5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;

[0152] d3)4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;

[0153] d4)5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;

[0154] d5)5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;

[0155] d6)4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;

[0156] d7)2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;

[0157] d8)2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;

[0158] d 9)5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;

[0159] d10)4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;

[0160] e 1)4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;

[0161] e2)4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole;

[0162] e3)4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino)thiazole;

[0163] e4)2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]thiazole;

[0164] e5)5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;

[0165] e6)1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene;

[0166] e7)4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide;

[0167] e8)5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene;

[0168] e9) 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonamide;

[0169] e 10)6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile;

[0170] f1)2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile;

[0171] f2)6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3-carbonitrile;

[0172] f3)4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

[0173] f4)4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

[0174] f5)4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

[0175] f6)3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

[0176] f7)2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

[0177] f8)2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

[0178] f9)2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

[0179] f10)4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

[0180] g1)2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

[0181] g2)4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

[0182] g3)2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1H-imidazole;

[0183] g4)2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazole;

[0184] g5)2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole;

[0185] g6)2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazole;

[0186] g7)1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole;

[0187] g8)2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole;

[0188] g9)4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

[0189] g10)2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

[0190] h1)4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

[0191] h2)2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole;

[0192] h3)4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;

[0193] h4)1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazole;

[0194] h5)4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;

[0195] h6)4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;

[0196] h7)4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;

[0197] h8)1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;

[0198] h10)4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzenesulfonamide;

[0199] i1)N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;

[0200] i2) ethyl[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate;

[0201] i3)4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-1H-pyrazole;

[0202] i4)4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole;

[0203] i5)1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;

[0204] i6)5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;

[0205] i7) 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;

[0206] i8)5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;

[0207] i9)2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;

[0208] i 10)5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine;

[0209] j1)2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;

[0210] j2)4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;

[0211] j3) 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;

[0212] j4)5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole;

[0213] j5) 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide;

[0214] j6) 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

[0215] j7) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

[0216] j8) 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide;

[0217] j9)1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0218] j10)1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0219] k1)1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0220] k2)1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0221] k3)1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0222] k4)1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0223] k5)1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0224] k6)4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide;

[0225] k7)1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0226] k8)4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide;

[0227] k9) 4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;

[0228] k10) 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide;

[0229] l1)1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0230] l2) 1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0231] l3)4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzenesulfonamide;

[0232] l4)1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

[0233] l5)4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;

[0234] l6)4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide;

[0235] l7) ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]-2-benzyl-acetate;

[0236] l8)2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]aceticacid;

[0237] l9)2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole;

[0238] l10)4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole;

[0239] m1)4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole; and

[0240] m2)4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfonamide.

[0241] m3) 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0242] m4)6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0243] m5)8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0244] m6)6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0245] m7)6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0246] m8) 2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid

[0247] m9)7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0248] m10) 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0249] n1) 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0250] n2)6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0251] n3) 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0252] n4) 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0253] n5) 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0254] n6)6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0255] n7)7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0256] n8) 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0257] n9)6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0258] n 10)6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0259] o1)6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0260] o2) 6,7-dichloro-2-trifluoromethyl-2H— 1-benzopyran-3-carboxylicacid;

[0261] o3) 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0262] o4) 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid;

[0263] o5)6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0264] o6) 8-chloro-6-methyl-2-trifluoromethyl-2H—1-benzopyran-3-carboxylic acid;

[0265] o7)8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0266] o8)6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0267] o9) 8-bromo-6-fluoro-2-trifluoromethyl-2H—1-benzopyran-3-carboxylic acid;

[0268] o10)8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0269] p1)8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0270] p2)6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0271] p3)6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0272] p4)6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0273] p5)6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0274] p6)6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0275] p7)6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0276] p8)6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0277] p9)6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0278] p10)6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0279] q1)8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0280] q2) 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0281] q3) 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0282] q4)8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0283] q5) 6,8-dichloro-(S)-2-trifluoromethyl-2H—1-benzopyran-3-carboxylic acid;

[0284] q6)6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0285] q7)6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0286] q8)6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0287] q9) 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0288] q 10)7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-carboxylicacid;

[0289] r1)5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulphonyl-2(5H)-fluranone;

[0290] r2) 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylicacid;

[0291] r3)4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0292] r4)4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0293] r5)4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0294] r6)3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

[0295] r7)2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

[0296] r8)4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

[0297] r9) 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

[0298] r10) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

[0299] s1)[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfonamide;

[0300] s2) 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; or

[0301] s3)4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfonamide;or a pharmaceutically acceptable salt or prodrug thereof.

[0302] In a further preferred embodiment of the invention thecyclooxygenase inhibitor can be selected from the class of tricycliccyclooxygenase-2 selective inhibitors represented by the generalstructure of formula VII:

[0303] wherein:

[0304] Z¹ is selected from the group consisting of partially unsaturatedor unsaturated heterocyclyl and partially unsaturated or unsaturatedcarbocyclic rings;

[0305] R²⁴ is selected from the group consisting of heterocyclyl,cycloalkyl, cycloalkenyl and aryl, wherein R²⁴ is optionally substitutedat a substitutable position with one or more radicals selected fromalkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;

[0306] R²⁵ is selected from the group consisting of methyl or amino; and

[0307] R²⁶ is selected from the group consisting of a radical selectedfrom H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl,heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl,haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl,alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl,aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl,aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl,alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino,N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl,alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy,aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl,N-alkyl-N-arylaminosulfonyl;

[0308] or a prodrug thereof.

[0309] In a preferred embodiment of the invention the cyclooxygenase-2selective inhibitor represented by the above Formula VII is selectedfrom the group of compounds, illustrated in Table 2, which includescelecoxib (B-18), valdecoxib (B-19), deracoxib (B-20), rofecoxib (B-21),etoricoxib (MK-663; B-22), JTE-522 (B-23), or a prodrug thereof.

[0310] Additional information about selected examples of the Cox-2selective inhibitors discussed above can be found as follows: celecoxib(CAS RN 169590-42-5, C-2779, SC-58653, and in U.S. Pat. No. 5,466,823);deracoxib (CAS RN 169590-41-4); rofecoxib (CAS RN 162011-90-7); compoundB-24 (U.S. Pat. No. 5,840,924); compound B-26 (WO 00/25779); andetoricoxib (CAS RN 202409-33-4, MK-663, SC-86218, and in WO 98/03484).TABLE 2 Examples of Tricyclic COX-2 Selective Inhibitors Compound NumberStructural Formula B-18

B-19

B-20

B-21

B-22

B-23

[0311] In a more preferred embodiment of the invention, the Cox-2selective inhibitor is selected from the group consisting of celecoxib,rofecoxib and etoricoxib.

[0312] In a preferred embodiment of the invention, parecoxib (See, e.g.U.S. Pat. No. 5,932,598), having the structure shown in B-24, which is atherapeutically effective prodrug of the tricyclic cyclooxygenase-2selective inhibitor valdecoxib, B-1 9, (See, e.g., U.S. Pat. No.5,633,272), may be advantageously employed as a source of acyclooxygenase inhibitor.

[0313] A preferred form of parecoxib is sodium parecoxib.

[0314] In another embodiment of the invention, the compound ABT-963having the formula B-25 that has been previously described inInternational Publication number WO 00/24719, is another tricycliccyclooxygenase-2 selective inhibitor which may be advantageouslyemployed.

[0315] In a further embodiment of the invention, the cyclooxygenaseinhibitor can be selected from the class of phenylacetic acid derivativecyclooxygenase-2 selective inhibitors represented by the generalstructure of Formula VIII:

[0316] wherein:

[0317] R²⁷ is methyl, ethyl, or propyl;

[0318] R²⁸ is chloro or fluoro;

[0319] R²⁹ is hydrogen, fluoro, or methyl;

[0320] R³⁰ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxyor hydroxy;

[0321] R³¹ is hydrogen, fluoro, or methyl; and

[0322] R³² is chloro, fluoro, trifluoromethyl, methyl, or ethyl,provided that R²⁸, R²⁹, R³⁰ and R³¹ are not all fluoro when R²⁷ is ethyland R³⁰ is H.

[0323] A phenylacetic acid derivative cyclooxygenase-2 selectiveinhibitor that is described in WO 99/11605 is a compound that has thestructure shown in Formula VIII,

[0324] wherein:

[0325] R²⁷ is ethyl;

[0326] R²⁸ and R³⁰ are chloro;

[0327] R²⁹ and R³¹ are hydrogen; and

[0328] R³² is methyl.

[0329] Another phenylacetic acid derivative cyclooxygenase-2 selectiveinhibitor is a compound that has the structure shown in Formula VIII,

[0330] wherein:

[0331] R²⁷ is propyl;

[0332] R²⁸ and R³⁰ are chloro;

[0333] R²⁹ and R³¹ are methyl; and

[0334] R³² is ethyl.

[0335] Another phenylacetic acid derivative cyclooxygenase-2 selectiveinhibitor that is described in WO 02/20090 is a compound that isreferred to as COX-189 (also termed lumiracoxib), having CAS Reg. No.220991-20-8, and having the structure shown in Formula VIII,

[0336] wherein:

[0337] R²⁷ is methyl;

[0338] R²⁸ is fluoro;

[0339] R³² is chloro; and

[0340] R²⁹ R³⁰, and R³¹ are hydrogen.

[0341] Compounds that have a structure similar to that shown in FormulaVIII, which can serve as the Cox-2 selective inhibitor of the presentinvention, are described in U.S. Pat. Nos. 6,310,099, 6,291,523, and5,958,978.

[0342] Other cyclooxygenase-2 selective inhibitors that can be used inthe present invention have the general structure shown in formula IX,where the J group is a carbocycle or a heterocycle. Preferredembodiments have the structure:

[0343] wherein:

[0344] X is O; J is 1-phenyl; R³³ is 2-NHSO₂CH₃; R³⁴ is 4-NO₂; and thereis no R³⁵ group, (nimesulide), and

[0345] X is O; J is 1-oxo-inden-5-yl; R³³ is 2-F; R³⁴ is 4-F; and R³⁵ is6-NHSO₂CH₃, (flosulide); and

[0346] X is O; J is cyclohexyl; R³³ is 2-NHSO₂CH₃; R³⁴ is 5-NO₂; andthere is no R³⁵ group, (NS-398); and

[0347] X is S; J is 1-oxo-inden-5-yl; R³³ is 2-F; R³⁴ is 4-F; and R³⁵ is6-N^(−SO) ₂CH₃ Na⁺, (L-745337); and

[0348] X is S; J is thiophen-2-yl; R³³ is 4-F; there is no R³⁴ group;and R³⁵ is 5-NHSO₂CH₃, (RWJ-63556); and

[0349] X is 0; J is2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)furan-(5H)-3-yl; R³³ is 3-F;R³⁴ is 4-F; and R³⁵ is 4-(p-SO₂CH₃)C₆H₄, (L-784512).

[0350] Further information on the applications of the Cox-2 selectiveinhibitor N-(2-cyclohexyloxynitrophenyl) methane sulfonamide (NS-398,CAS RN 123653-11-2), having a structure as shown in formula B-26, havebeen described by, for example, Yoshimi, N. et al., in Japanese J.Cancer Res., 90(4):406-412 (1999); Falgueyret, J.-P. et al., in ScienceSpectra, available at:http://www.gbhap.com/Science_Spectra/20-1-article.htm (06/06/2001); andIwata, K. et al., in Jpn. J. Pharmacol., 75(2):191-194 (1997).

[0351] An evaluation of the anti-inflammatory activity of thecyclooxygenase-2 selective inhibitor, RWJ 63556, in a canine model ofinflammation, was described by Kirchner et al., in J Pharmacol Exp Ther282, 1094-1101 (1997).

[0352] Materials that can serve as the cyclooxygenase-2 selectiveinhibitor of the present invention include diarylmethylidenefuranderivatives that are described in U.S. Pat. No. 6,180,651. Suchdiarylmethylidenefuran derivatives have the general formula shown belowin formula X:

[0353] wherein:

[0354] the rings T and M independently are:

[0355] a phenyl radical,

[0356] a naphthyl radical,

[0357] a radical derived from a heterocycle comprising 5 to 6 membersand possessing from 1 to 4 heteroatoms, or

[0358] a radical derived from a saturated hydrocarbon ring having from 3to 7 carbon atoms;

[0359] at least one of the substituents Q¹, Q², L¹ or L² is:

[0360] an —S(O)_(n)—R group, in which n is an integer equal to 0, 1 or 2and R is:

[0361] a lower alkyl radical having 1 to 6 carbon atoms or

[0362] a lower haloalkyl radical having 1 to 6 carbon atoms, or

[0363] an —SO₂NH₂ group;

[0364] and is located in the para position,

[0365] the others independently being:

[0366] a hydrogen atom,

[0367] a halogen atom,

[0368] a lower alkyl radical having 1 to 6 carbon atoms,

[0369] a trifluoromethyl radical, or

[0370] a lower O-alkyl radical having 1 to 6 carbon atoms, or

[0371] Q¹ and Q² or L¹ and L² are a methylenedioxy group; and

[0372] R³⁶, R³⁷, R³⁸ and R³⁹ independently are:

[0373] a hydrogen atom,

[0374] a halogen atom,

[0375] a lower alkyl radical having 1 to 6 carbon atoms,

[0376] a lower haloalkyl radical having 1 to 6 carbon atoms, or

[0377] an aromatic radical selected from the group consisting of phenyl,naphthyl, thienyl, furyl and pyridyl; or,

[0378] R³⁶, R³⁷ or R³⁸, R³⁹ are an oxygen atom, or

[0379] R³⁶, R³⁷ or R³⁸, R³⁹, together with the carbon atom to which theyare attached, form a saturated hydrocarbon ring having from 3 to 7carbon atoms;

[0380] or an isomer or prodrug thereof.

[0381] Particular materials that are included in this family ofcompounds, and which can serve as the cyclooxygenase-2 selectiveinhibitor in the present invention, includeN-(2-cyclohexyloxynitrophenyl)methane sulfonamide, and(E)-4-[(4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene)methyl]benzenesulfonamide.

[0382] Cyclooxygenase-2 selective inhibitors that are useful in thepresent invention include darbufelone (Pfizer), CS-502 (Sankyo), LAS34475 (Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516(Servier), SD 8381 (Pharmacia, described in U.S. Pat. No. 6,034,256),BMS-347070 (Bristol Myers Squibb, described in U.S. Pat. No. 6,180,651),MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1367 (Chiroscience),L-748731 (Merck), CT3 (Atlantic Pharmaceutical), CGP-28238 (Novartis),BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome),6-dioxo-9H-purin-8-yl-cinnamic acid (Glaxo Wellcome), and S-2474(Shionogi).

[0383] Information about S-33516, mentioned above, can be found inCurrent Drugs Headline News, athttp://www.current-drugs.com/NEWS/Inflam1.htm, 10/04/2001, where it wasreported that S-33516 is a tetrahydroisoinde derivative which has IC₅₀values of 0.1 and 0.001 mM against cyclooxygenase-1 andcyclooxygenase-2, respectively. In human whole blood, S-33516 wasreported to have an ED₅₀=0.39 mg/kg.

[0384] Compounds that may act as cyclooxygenase-2 selective inhibitorsinclude multibinding compounds containing from 2 to 10 ligandscovanlently attached to one or more linkers, as described in U.S. Pat.No. 6,395,724.

[0385] Compounds that may act as cyclooxygenase-2 inhibitors includeconjugated linoleic acid that is described in U.S. Pat. No. 6,077,868.

[0386] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include heterocyclic aromatic oxazolecompounds that are described in U.S. Pat. Nos. 5,994,381 and 6,362,209.Such heterocyclic aromatic oxazole compounds have the formula shownbelow in formula XI:

[0387] wherein:

[0388] Z² is an oxygen atom;

[0389] one of R⁴⁰ and R⁴¹ is a group of the formula

[0390] wherein:

[0391] R⁴³ is lower alkyl, amino or lower alkylamino; and

[0392] R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ are the same or different and each ishydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl,hydroxy or amino, provided that at least one of R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ isnot hydrogen atom, and the other is an optionally substitutedcycloalkyl, an optionally substituted heterocyclic group or anoptionally substituted aryl; and

[0393] R³⁰ is a lower alkyl or a halogenated lower alkyl, and apharmaceutically acceptable salt thereof.

[0394] Cox-2 selective inhibitors that are useful in the subject methodand compositions can include compounds that are described in U.S. Pat.Nos. 6,080,876 and 6,133,292, and described by formula XII:

[0395] wherein:

[0396] Z³ is selected from the group consisting of:

[0397] (a) linear or branched C₁₋₆ alkyl,

[0398] (b) linear or branched C₁₋₆ alkoxy,

[0399] (c) unsubstituted, mono-, di- or tri-substituted phenyl ornaphthyl wherein the substituents are selected from the group consistingof:

[0400] (1) hydrogen,

[0401] (2) halo,

[0402] (3) C₁₋₃ alkoxy,

[0403] (4) CN,

[0404] (5) C₁₋₃ fluoroalkyl

[0405] (6) C₁₋₃ alkyl,

[0406] (7) —CO₂H;

[0407] R⁴⁸ is selected from the group consisting of NH₂ and CH₃,

[0408] R⁴⁹ is selected from the group consisting of:

[0409] C₁₋₆ alkyl unsubstituted or substituted with C₃₋₆ cycloalkyl, andC₃₋₆ cycloalkyl;

[0410] R⁵⁰ is selected from the group consisting of:

[0411] C₁₋₆ alkyl unsubstituted or substituted with one, two or threefluoro atoms; and

[0412] C₃₋₆ cycloalkyl;

[0413] with the proviso that R⁴⁹ and R⁵⁰ are not the same.

[0414] Materials that can serve as cyclooxygenase-2 selective inhibitorsinclude pyridines that are described in U.S. Pat. Nos. 6,369,275,6,127,545, 6,130,334, 6,204,387, 6,071,936, 6,001,843 and 6,040,450, andwhich have the general formula described by formula XIII:

[0415] wherein:

[0416] R⁵′ is selected from the group consisting of:

[0417] (a) CH₃,

[0418] (b) NH₂,

[0419] (c) NHC(O)CF₃,

[0420] (d) NHCH₃;

[0421] Z⁴ is a mono-, di-, or trisubstituted phenyl or pyridinyl (or theN-oxide thereof,

[0422] wherein the substituents are chosen from the group consisting of:

[0423] (a) hydrogen,

[0424] (b) halo,

[0425] (c) C₁₋₆ alkoxy,

[0426] (d) C₁₋₆ alkylthio,

[0427] (e) CN,

[0428] (f) C₁₋₆ alkyl,

[0429] (g) C₁₋₆ fluoroalkyl,

[0430] (h) N₃,

[0431] (i) —CO₂R⁵³,

[0432] (j) hydroxy,

[0433] (k) —C(R⁵⁴)(R⁵⁵)—OH,

[0434] (l) —C₁₋₆alkyl-CO₂—R⁵⁶,

[0435] (m) C₁₋₆fluoroalkoxy;

[0436] R⁵² is chosen from the group consisting of:

[0437] (a) halo,

[0438] (b) C₁₋₁₆alkoxy,

[0439] (c) C₁₋₆ alkylthio,

[0440] (d) CN,

[0441] (e) C₁₋₆ alkyl,

[0442] (f) C₁₋₆ fluoroalkyl,

[0443] (g) N₃,

[0444] (h) —CO₂R⁵⁷,

[0445] (i) hydroxy,

[0446] (j) —C(R⁵⁸)(R⁵⁹)—OH,

[0447] (k) —C₁₋₆alkyl-CO₂—R⁶⁰,

[0448] (l) C₁₋₆fluoroalkoxy,

[0449] (m) NO₂,

[0450] (n) NR⁶¹R⁶², and

[0451] (o) NHCOR⁶³;

[0452] R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸ R⁵⁹ R⁶⁰ R⁶¹, R⁶², R⁶³, are eachindependently chosen from the group consisting of:

[0453] (a) hydrogen, and

[0454] (b) C₁₋₆alkyl;

[0455] or R⁵⁴ and R⁵⁵, R⁵⁸ and R⁵⁹ or R⁶¹ and R⁶² together with the atomto which they are attached form a saturated monocyclic ring of 3, 4, 5,6, or 7 atoms.

[0456] Materials that can serve as the cyclooxygenase-2 selectiveinhibitor of the present invention include diarylbenzopyran derivativesthat are described in U.S. Pat. No. 6,340,694. Such diarylbenzopyranderivatives have the general formula shown below in formula XIV:

[0457] wherein:

[0458] X⁸ is an oxygen atom or a sulfur atom;

[0459] R⁶⁴ and R⁶⁵, identical to or different from each other, areindependently a hydrogen atom, a halogen atom, a C₁-C₆ lower alkylgroup, a trifluoromethyl group, an alkoxy group, a hydroxy group, anitro group, a nitrile group, or a carboxyl group;

[0460] R⁶⁶ is a group of a formula: S(O)NR⁶⁸ wherein n is an integer of0-2, R⁶⁸ is a hydrogen atom, a C₁-C₆ lower alkyl group, or a group of aformula: NR⁶⁹ R⁷⁰ wherein R⁶⁹ and R⁷⁰, identical to or different fromeach other, are independently a hydrogen atom, or a C₁-C₆ lower alkylgroup; and

[0461] R⁶⁷ is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl,thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolylsubstituted with a C₁-C₆ lower alkyl group, indanyl, pyrazinyl, or asubstituted group represented by the following structures:

[0462] wherein:

[0463] R⁷¹ through R⁷⁵, identical to or different from one another, areindependently a hydrogen atom, a halogen atom, a C₁-C₆ lower alkylgroup, a trifluoromethyl group, an alkoxy group, a hydroxy group, ahydroxyalkyl group, a nitro group, a group of a formula: S(O)NR⁶⁸, agroup of a formula: NR⁶⁹ R⁷⁰, a trifluoromethoxy group, a nitrile groupa carboxyl group, an acetyl group, or a formyl group,

[0464] wherein n, R⁶⁸, R⁶⁹ and R⁷⁰ have the same meaning as defined byR⁶⁶ above; and

[0465] R⁷⁶ is a hydrogen atom, a halogen atom, a C₁-C₆ lower alkylgroup, a trifluoromethyl group, an alkoxy group, a hydroxy group, atrifluoromethoxy group, a carboxyl group, or an acetyl group.

[0466] Materials that can serve as the cyclooxygenase-2 selectiveinhibitor of the present invention include1-(4-sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines that are describedin U.S. Pat. No. 6,376,519. Such1-(4-sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines have the formulashown below in formula XV:

[0467] wherein:

[0468] X⁹ is selected from the group consisting of C₁-C₆ trihalomethyl,preferably trifluoromethyl; C₁-C₆ alkyl; and an optionally substitutedor di-substituted phenyl group of formula XVI:

[0469] wherein:

[0470] R⁷⁷ and R⁷⁸ are independently selected from the group consistingof hydrogen, halogen, preferably chlorine, fluorine and bromine;hydroxyl; nitro; C₁-C₆ alkyl, preferably C₁-C₃ alkyl; C₁-C₆ alkoxy,preferably C₁-C₃ alkoxy; carboxy; C₁-C₆ trihaloalkyl, preferablytrihalomethyl, most preferably trifluoromethyl; and cyano;

[0471] Z⁵ is selected from the group consisting of substituted andunsubstituted aryl.

[0472] Materials that can serve as the cyclooxygenase-2 selectiveinhibitor of the present invention include heterocycles that aredescribed in U.S. Pat. No. 6,153,787. Such heterocycles have the generalformulas shown below in formulas XVII and XVIII:

[0473] wherein:

[0474] R⁷⁹ is a mono-, di-, or tri-substituted C₁₋₁₂ alkyl, or a mono-,or an unsubstituted or mono-, di- or tri-substituted linear or branchedC₂₋₁₀ alkenyl, or an unsubstituted or mono-, di- or tri-substitutedlinear or branched C₂₋₁₀ alkynyl, or an unsubstituted or mono-, di- ortri-substituted C₃₋₁₂ cycloalkenyl, or an unsubstituted or mono-, di- ortri-substituted C₅₋₁₂ cycloalkynyl, wherein the substituents are chosenfrom the group consisting of:

[0475] (a) halo, selected from F, Cl, Br, and I,

[0476] (b) OH,

[0477] (c) CF₃,

[0478] (d) C₃₋₆ cycloalkyl,

[0479] (e)=O,

[0480] (f) dioxolane,

[0481] (g) CN; and

[0482] R⁸⁰ is selected from the group consisting of:

[0483] (a) CH₃,

[0484] (b) NH₂,

[0485] (c) NHC(O)CF₃,

[0486] (d) NHCH₃;

[0487] R⁸¹ and R⁸² are independently chosen from the group consistingof:

[0488] (a) hydrogen,

[0489] (b) C₁₋₁₀ alkyl;

[0490] or R⁸¹ and R⁸² together with the carbon to which they areattached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7atoms.

[0491] Formula XVIII is:

[0492] X¹⁰ is fluoro or chloro.

[0493] Materials that can serve as the cyclooxygenase-2 selectiveinhibitor of the present invention include 2,3,5-trisubstitutedpyridines that are described in U.S. Pat. No. 6,046,217. Such pyridineshave the general formula shown below in formula XIX:

[0494] or a pharmaceutically acceptable salt thereof,

[0495] wherein:

[0496] X¹¹ is selected from the group consisting of:

[0497] (a) O,

[0498] (b) S,

[0499] (c) bond;

[0500] n is 0 or 1;

[0501] R⁸³ is selected from the group consisting of:

[0502] (a) CH₃,

[0503] (b) NH₂,

[0504] (c) NHC(O)CF₃;

[0505] R⁸⁴ is chosen from the group consisting of:

[0506] (a) halo,

[0507] (b) C₁₋₆ alkoxy,

[0508] (c) C₁₋₆ alkylthio,

[0509] (d) CN,

[0510] (e) C₁₋₆ alkyl,

[0511] (f) C₁₋₆ fluoroalkyl,

[0512] (g) N₃,

[0513] (h) —CO₂ R⁹²,

[0514] (i) hydroxy,

[0515] (j) —C(R⁹³)(R⁹⁴)—OH,

[0516] (k) —C₁₋₆ alkyl-CO₂-R⁹⁵,

[0517] (l) C₁₋₆ fluoroalkoxy,

[0518] (m) NO₂,

[0519] (n) NR⁹⁶ R⁹⁷,

[0520] (o) NHCOR⁹⁸;

[0521] R⁸⁵ to R⁹⁸ are independantly chosen from the group consisting of

[0522] (a) hydrogen,

[0523] (b) C₁₋₆ alkyl;

[0524] or R⁸⁵ and R⁸⁹, or R⁸⁹ and R⁹⁰ together with the atoms to whichthey are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, orR⁸⁵ and R⁸⁷ are joined to form a bond.

[0525] One preferred embodiment of the Cox-2 selective inhibitor offormula XIX is that wherein X is a bond.

[0526] Another preferred embodiment of the Cox-2 selective inhibitor offormula XIX is that wherein X is 0.

[0527] Another preferred embodiment of the Cox-2 selective inhibitor offormula XIX is that wherein X is S.

[0528] Another preferred embodiment of the Cox-2 selective inhibitor offormula XIX is that wherein R⁸³ is CH₃.

[0529] Another preferred embodiment of the Cox-2 selective inhibitor offormula XIX is that wherein R⁸⁴ is halo or C₁₋₆ fluoroalkyl.

[0530] Materials that can serve as the cyclooxygenase-2 selectiveinhibitor of the present invention include diaryl bicyclic heterocyclesthat are described in U.S. Pat. No. 6,329,421. Such diaryl bicyclicheterocycles have the general formula shown below in formula XX:

[0531] and pharmaceutically acceptable salts thereof wherein:

[0532] -A⁵=A⁶_A⁷=A⁸- is selected from the group consisting of:

[0533] (a) —CH═CH—CH═CH—,

[0534] (b) —CH₂—CH₂—CH₂—C(O)—, —CH₂—CH₂—C(O)—CH₂—, —CH₂—C(O)—CH₂—CH₂,—C(O)—CH₂—CH₂—CH₂,

[0535] (c) —CH₂—CH₂—C(O)—, —CH₂—C(O)—CH₂—, —C(O)—CH₂—CH₂,

[0536] (d) —CH₂—CH₂—O—C(O)—, CH₂—O—C(O)—CH₂—O—C(O)—CH₂—CH₂—,

[0537] (e) —CH₂—CH₂—C(O)—O—, —CH₂—C(O)—OCH₂—C(O)—O—CH₂—CH₂—,

[0538] (f) —C(R¹⁰⁵)₂—O—C(O)—, —C(O)—O—C(R¹⁰⁵)₂—, —C(O)—C(R¹⁰⁵)₂—,—C(R¹⁰⁵)₂—C(O)—O—,

[0539] (g) —N═CH—CH═CH—,

[0540] (h) —CH═N—CH═CH—,

[0541] (i) —CH═CH—N═CH—,

[0542] (j) —CH═CH—CH═N—,

[0543] (k) —N═CH—CH═N—,

[0544] (l) —N═CH—N═CH—,

[0545] (m) —CH═N—CH═N—,

[0546] (n) —S—CH═N—,

[0547] (o) —S—N═CH—,

[0548] (p) —N═N—NH—,

[0549] (q) —CH═N—S—, and

[0550] (r) —N═CH—S—;

[0551] R⁹⁹ is selected from the group consisting of:

[0552] (a) S(O)₂ CH₃,

[0553] (b) S(O)₂ NH₂,

[0554] (c) S(O)₂ NHCOCF₃,

[0555] (d) S(O)(NH)CH₃,

[0556] (e) S(O)(NH)NH₂,

[0557] (f) S(O)(NH)NHCOCF₃,

[0558] (g) P(O)(CH₃)OH, and

[0559] (h) P(O)(CH₃)NH₂;

[0560] R¹⁰⁰ is selected from the group consisting of:

[0561] (a) C₁₋₆ alkyl,

[0562] (b) C₃₋₇, cycloalkyl,

[0563] (c) mono- or di-substituted phenyl or naphthyl wherein thesubstituent is selected from the group consisting of:

[0564] (1) hydrogen,

[0565] (2) halo, including F, Cl, Br, I,

[0566] (3) C₁₋₆ alkoxy,

[0567] (4) C₁₋₆ alkylthio,

[0568] (5) CN,

[0569] (6) CF₃,

[0570] (7) C₁₋₆ alkyl,

[0571] (8) N₃,

[0572] (9) —CO₂H,

[0573] (10)—CO₂—C₁₋₄ alkyl,

[0574] (11) —C(R¹⁰³)(R¹⁰⁴)—OH,

[0575] (12) —C(R¹⁰³)(R¹⁰⁴)—O—C₁₋₄ alkyl, and

[0576] (13)—C₁₋₆ alkyl-CO₂-R¹⁰⁶;

[0577] (d) mono- or di-substituted heteroaryl wherein the heteroaryl isa monocyclic aromatic ring of 5 atoms, said ring having one hetero atomwhich is S, O, or N, and optionally 1, 2, or 3 additional N atoms; orthe heteroaryl is a monocyclic ring of 6 atoms, said ring having onehetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms;said substituents are selected from the group consisting of:

[0578] (1) hydrogen,

[0579] (2) halo, including fluoro, chloro, bromo and iodo,

[0580] (3) C₁₋₆ alkyl,

[0581] (4) C₁₋₆ alkoxy,

[0582] (5) C₁₋₆ alkylthio,

[0583] (6) CN,

[0584] (7) CF₃,

[0585] (8) N₃,

[0586] (9) —C(R¹⁰³)(R¹⁰⁴)—OH, and

[0587] (10) —C(R¹⁰³)(R¹⁰⁴)—O—C₁₋₄ alkyl;

[0588] (e) benzoheteroaryl which includes the benzo fused analogs of(d);

[0589] R¹⁰¹ and R¹⁰² are the substituents residing on any position of-A⁵=A⁶-A⁷=A⁸- and are selected independently from the group consistingof:

[0590] (a) hydrogen,

[0591] (b) CF₃,

[0592] (c) CN,

[0593] (d) C₁₋₆ alkyl,

[0594] (e) Q3 wherein Q3 is Q⁴, CO₂H, C(R¹⁰³)(R¹⁰⁴)OH,

[0595] (f) —O-Q⁴,

[0596] (g) —S-Q⁴, and

[0597] (h) optionally substituted:

[0598] (1) —C₁₋₅ alkyl-Q³,

[0599] (2) —O—C₁₋₅ alkyl-Q³,

[0600] (3) —S—C₁₋₅ alkyl-Q³,

[0601] (4) —C-3 alkyl-O—C₁₋₃ alkyl-Q³,

[0602] (5) —C₁₋₃ alkyl-S—C₁₋₃ alkyl-Q³,

[0603] (6) —C₁₋₅ alkyl-O-Q⁴,

[0604] (7) —C₁₋₅ alkyl-S-Q⁴,

[0605] wherein the substituent resides on the alkyl chain and thesubstituent is C₁₋₃ alkyl, and Q³ is Q4, CO₂H, C(R¹⁰³)(R¹⁰⁴)OH Q⁴ isCO₂—C₁₋₄ alkyl, tetrazolyl-5-yl, or C(R¹⁰³)(R¹⁰⁴)O—C₁₋₄ alkyl;

[0606] R¹⁰³, R¹⁰⁴ and R¹⁰⁵ are each independently selected from thegroup consisting of

[0607] (a) hydrogen,

[0608] (b) C₁₋₆ alkyl; or

[0609] R¹⁰³ and R¹⁰⁴ together with the carbon to which they are attachedform a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms, or twoR¹⁰⁵ groups on the same carbon form a saturated monocyclic carbon ringof 3, 4, 5, 6 or 7 atoms;

[0610] R¹⁰⁶ is hydrogen or C₁₋₆ alkyl;

[0611] R¹⁰⁷ is hydrogen, C₁₋₆ alkyl or aryl;

[0612] X⁷ is O, S, NR¹⁰⁷, CO, C(R¹⁰⁷)₂, C(R¹⁰⁷)(OH), —C(R⁰⁷)═C(R⁰⁷)—;—C(R¹⁰⁷)═N—; —N═C(R¹⁰⁷)-.

[0613] Compounds that may act as cyclooxygenase-2 inhibitors includesalts of 5-amino or a substituted amino 1,2,3-triazole compound that aredescribed in U.S. Pat. No. 6,239,137. The salts are of a class ofcompounds of formula XXI:

[0614] wherein:

[0615] R¹⁰⁸ is:

[0616] wherein:

[0617] p is 0 to 2; m is 0 to 4; and n is 0 to 5; X¹³ is O, S, SO, SO₂,CO, CHCN, CH₂ or C═NR¹¹³ where R¹¹³ is hydrogen, loweralkyl, hydroxy,loweralkoxy, amino, loweralkylamino, diloweralkylamino or cyano; and,R¹¹¹ and R¹¹² are independently halogen, cyano, trifluoromethyl,loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy,trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl,loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio,trifluoromethylsulfinyl, or trifluoromethylsulfonyl; R¹⁰⁹ is amino, monoor diloweralkyl amino, acetamido, acetimido, ureido, formamido,formamido or guanidino; and R¹¹⁰ is carbamoyl, cyano, carbazoyl, amidinoor N-hydroxycarbamoyl; wherein the loweralkyl, loweralkyl containing,loweralkoxy and loweralkanoyl groups contain from 1 to 3 carbon atoms.

[0618] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include pyrazole derivatives that aredescribed in U.S. Pat. No. 6,136,831. Such pyrazole derivatives have theformula shown below in formula XXII:

[0619] wherein:

[0620] R¹¹⁴ is hydrogen or halogen, R¹¹⁵ and R¹¹⁶ are each independentlyhydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or loweralkanoyloxy;

[0621] R¹¹⁷ is lower haloalkyl or lower alkyl;

[0622] X¹⁴ is sulfur, oxygen or NH; and

[0623] Z⁶ is lower alkylthio, lower alkylsulfonyl or sulfamoyl; or apharmaceutically acceptable salt thereof.

[0624] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include substituted derivatives ofbenzosulphonamides that are described in U.S. Pat. No. 6,297,282. Suchbenzosulphonamide derivatives have the formula shown below in formulaXXIII:

[0625] wherein:

[0626] X¹⁵ denotes oxygen, sulphur or NH;

[0627] R¹¹⁸ is an optionally unsaturated alkyl or alkyloxyalkyl group,optionally mono- or polysubstituted or mixed substituted by halogen,alkoxy, oxo or cyano, a cycloalkyl, aryl or heteroaryl group optionallymono- or polysubstituted or mixed substituted by halogen, alkyl, CF₃,cyano or alkoxy;

[0628] R¹¹⁹ and R¹²⁰, independently from one another, denote hydrogen,an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroarylgroup or a group (CH₂)_(n)—X¹⁶; or

[0629] R¹¹⁹ and R¹²⁰, together with the N— atom, denote a 3 to7-membered, saturated, partially or completely unsaturated heterocyclewith one or more heteroatoms N, O or S, which can optionally besubstituted by oxo, an alkyl, alkylaryl or aryl group, or a group(CH₂)_(n)—X¹⁶;

[0630]  X¹⁶ denotes halogen, NO₂, —OR¹²¹, —COR¹²¹, —CO₂ R¹²¹, —OCO₂R¹²¹, —CN, —CONR¹²¹ OR¹²²-CONR²¹ R¹²², —SR²¹, —S(O)R¹²¹, —S(O)₂ R¹²¹,—NR¹²¹ R¹²², —NHC(O)R¹²¹, —NHS(O)₂ R¹²¹;

[0631]  n denotes a whole number from 0 to 6;

[0632] R¹²³ denotes a straight-chained or branched alkyl group with 1-10C— atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group,aralkyl group, a heteroaryl or heteroaralkyl group which can optionallybe mono- or polysubstituted or mixed substituted by halogen or alkoxy;

[0633] R¹²⁴ denotes halogen, hydroxy, a straight-chained or branchedalkyl, alkoxy, acyloxy or alkyloxycarbonyl group with 1-6 C— atoms,which can optionally be mono- or polysubstituted by halogen, NO₂,—OR¹²¹, COR¹², —CO₂ R 121 OCO₂ R¹²¹, —CN, —CONR¹²¹ OR¹²², —CONR¹² R¹,—SR¹²¹, —S(O)R, —S(O)₂ R¹²¹1-NR¹²¹ R¹²² ₇—NHC(O)R¹²¹, NHS(O)₂ R¹²¹, or apolyfluoroalkyl group;

[0634] R¹²¹ and R²², independently from one another, denote hydrogen,alkyl, aralkyl or aryl; and

[0635] m denotes a whole number from 0 to 2;

[0636] and the pharmaceutically-acceptable salts thereof.

[0637] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include3-phenyl-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanones that are describedin U.S. Pat. No. 6,239,173. Such3-phenyl-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanones have the formulashown below in formula XXIV:

[0638] or pharmaceutically acceptable salts thereof wherein:

[0639] X¹⁷—Y¹-Z⁷-is selected from the group consisting of:

[0640] (a) —CH₂ CH₂ CH₂—,

[0641] (b) —C(O)CH₂ CH₂—,

[0642] (c) —CH₂ CH₂ C(O)—,

[0643] (d) —CR¹²⁹ (R¹²⁹′)—O—C(O)—,

[0644] (e) —C(O)—O—CR¹²⁹ (R^(129′))—,

[0645] (f) —CH₂—NR¹²⁷-CH₂—,

[0646] (g) —CR¹²⁹ (R¹²⁹′)—NR¹²⁷—C(O)—,

[0647] (h) —CR¹²⁸=CR^(128′)—S—

[0648] (i) —S—CR¹²⁸=CR^(128′)—,

[0649] (j) —S—N═CH—,

[0650] (k) —CH═N—S—,

[0651] (l) —N═CR¹²⁸—O—,

[0652] (m) —O—CR4=N—,

[0653] (n) —N═CR¹²⁸-NH—,

[0654] (o) —N═CR¹²⁸-S—, and

[0655] (p) —S—CR¹²⁸═N—,

[0656] (q) —C(O)—NR¹²⁷-CR¹²⁹ (R^(129′))—,

[0657] (r) —R¹²⁷ N—CH═CH— provided R₁₂₂ is not —S(O)₂CH₃,

[0658] (s) —CH═CH—NR¹²⁷ _provided R¹²⁵ is not —S(O)₂CH₃,

[0659] when side b is a double bond, and sides a and c are single bonds;and

[0660] X¹⁷—Y¹—Z⁷— is selected from the group consisting of:

[0661] (a)=CH—O—CH═, and

[0662] (b)=CH—NR¹²⁷-CH═,

[0663] (c) ═N—S—CH═,

[0664] (d)=CH—S—N═,

[0665] (e) ═N—O—CH═,

[0666] (f) ═CH—O—N═,

[0667] (g) ═N—S—N═,

[0668] (h) ═N—O—N═,

[0669] when sides a and c are double bonds and side b is a single bond;

[0670] R¹²⁵ is selected from the group consisting of:

[0671] (a) S(O)₂ CH₃,

[0672] (b) S(O)₂ NH₂,

[0673] (c) S(O)₂ NHC(O)CF₃,

[0674] (d) S(O)(NH)CH₃,

[0675] (e) S(O)(NH)NH₂,

[0676] (f) S(O)(NH)NHC(O)CF₃,

[0677] (g) P(O)(CH₃)OH, and

[0678] (h) P(O)(CH₃)NH₂;

[0679] R¹²⁶ is selected from the group consisting of

[0680] (a) C₁₋₆ alkyl,

[0681] (b) C₃, C₄, C₅, C₆, and C₇, cycloalkyl,

[0682] (c) mono-, di- or tri-substituted phenyl or naphthyl,

[0683]  wherein the substituent is selected from the group consistingof:

[0684] (1) hydrogen,

[0685] (2) halo,

[0686] (3) C₁₋₆ alkoxy,

[0687] (4) C₁₋₆ alkylthio,

[0688] (5) CN,

[0689] (6) CF₃,

[0690] (7) C₁₋₆ alkyl,

[0691] (8) N₃,

[0692] (9) —CO₂H,

[0693] (10) —CO₂—C₁₋₄ alkyl,

[0694] (11) —C(R¹²⁹)(R¹³⁰)—OH,

[0695] (12) —C(R¹²⁹)(R³⁰)—O—C₁₋₄ alkyl, and

[0696] (13) —C₁₋₆ alkyl-CO₂-R¹²⁹,

[0697] (d) mono-, di- or tri-substituted heteroaryl wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone hetero atom which is S, O, or N, and optionally 1, 2, or 3additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one hetero atom which is N, and optionally 1, 2, 3, or4 additional N atoms; said substituents are selected from the groupconsisting of:

[0698] (1) hydrogen,

[0699] (2) halo, including fluoro, chloro, bromo and iodo,

[0700] (3) C₁₋₆ alkyl,

[0701] (4) C₁₋₆ alkoxy,

[0702] (5) C₁₋₆ alkylthio,

[0703] (6) CN,

[0704] (7) CF₃,

[0705] (8) N₃,

[0706] (9) —C(R¹²⁹)(R¹³⁰)—OH, and

[0707] (10) —C(R¹²⁹)(R¹³⁰)—O—C₁₋₄ alkyl;

[0708] (e) benzoheteroaryl which includes the benzo fused analogs of(d);

[0709] R¹²⁷ is selected from the group consisting of:

[0710] (a) hydrogen,

[0711] (b) CF₃,

[0712] (c) CN,

[0713] (d) C₁₋₆ alkyl,

[0714] (e) hydroxyC₁₋₆ alkyl,

[0715] (f) —C(O)—C₁₋₆ alkyl,

[0716] (g) optionally substituted:

[0717] (1) —C₁₋₅ alkyl-Q⁵,

[0718] (2) —C₁₋₃ alkyl-O—C₁₋₃ alkyl-Q⁵,

[0719] (3) —C₁₋₃ alkyl-S—C₁₋₃ alkyl-Q⁵,

[0720] (4) —C₁₋₅ alkyl-O-Q⁵, or

[0721] (5) —C₁₋₅ alkyl-S-Q⁵,

[0722]  wherein the substituent resides on the alkyl and the substituentis C₁₋₃ alkyl;

[0723] (h) -Q⁵;

[0724] R¹²⁸ and R^(128′) are each independently selected from the groupconsisting of:

[0725] (a) hydrogen,

[0726] (b) CF₃,

[0727] (c) CN,

[0728] (d) C₁₋₆ alkyl,

[0729] (e) -Q⁵,

[0730] (f) —O-Q⁵;

[0731] (g) —S-Q⁵, and

[0732] (h) optionally substituted:

[0733] (1) —C₁₋₅ alkyl-Q⁵,

[0734] (2) —O—C₁₋₅ alkyl-Q⁵,

[0735] (3) —S—C₁₋₅ alkyl-Q⁵,

[0736] (4) —C₁₋₃ alkyl-O—C₁₋₃ alkyl-Q⁵,

[0737] (5) —C₁₋₃ alkyl-S—C₁₋₃ alkyl-Q⁵,

[0738] (6) —C₁₋₅ alkyl-O-Q⁵,

[0739] (7) —C₁₋₅ alkyl-S-Q⁵,

[0740]  wherein the substituent resides on the alkyl and the substituentis C₁₋₃ alkyl, and

[0741] R¹²⁹, R¹²⁹, R¹³⁰, R¹³¹ and R¹³² are each independently selectedfrom the group consisting of:

[0742] (a) hydrogen,

[0743] (b) C₁₋₆ alkyl;

[0744] or R¹²⁹ and R¹³⁰ or R¹³¹ and R¹³² together with the carbon towhich they are attached form a saturated monocyclic carbon ring of 3, 4,5, 6 or 7 atoms;

[0745] Q⁵ is CO₂H, CO₂—C₁₋₄ alkyl, tetrazolyl-5-yl, C(R¹³¹)(R¹³²)(OH),or C(R³¹)(R³²)(O—C₁₋₄ alkyl);

[0746] provided that when X-Y-Z is —S—CR¹²⁸=CR¹²⁸ then R¹²⁸ and R¹²⁸′are other than CF₃.

[0747] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include bicycliccarbonyl indolecompounds that are described in U.S. Pat. No. 6,303,628. Suchbicycliccarbonyl indole compounds have the formula shown below informula XXV:

[0748] or the pharmaceutically acceptable salts thereof wherein

[0749] A⁹ is C₁₋₆ alkylene or —NR¹³³—;

[0750] Z⁸ is C(=L³)R¹³⁴ or SO₂ R¹³⁵;

[0751] Z⁹ is CH or N;

[0752] Z¹⁰ and Y² are independently selected from —CH₂—, O, S and —

[0753] N—R¹³³;

[0754] m is 1, 2 or 3;

[0755] q and r are independently 0, 1 or 2;

[0756] X¹⁸ is independently selected from halogen, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino andcyano;

[0757] n is 0, 1, 2, 3 or 4;

[0758] L³ is oxygen or sulfur;

[0759] R¹³³ is hydrogen or C₁₋₄ alkyl;

[0760] R¹³⁴ is hydroxy, C₁₋₆ alkyl, halo-substituted C₁₋₆ alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆ alkoxy, C₃₋₇ cycloalkoxy, C₁₋₁₄ alkyl(C₃₋₇cycloalkoxy), —NR¹³⁶ R¹³⁷, C₄ alkylphenyl-O— or phenyl-O—, said phenylbeing optionally substituted with one to five substituents independentlyselected from halogen, C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy and nitro;

[0761]  R¹³⁵ is C₁₋₆ alkyl or halo-substituted C₁₋₆ alkyl; and

[0762] R¹³⁶ and R¹³⁷ are independently selected from hydrogen, C₁₋₆alkyl and halo-substituted C₁₋₆ alkyl.

[0763] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include benzimidazole compounds thatare described in U.S. Pat. No. 6,310,079. Such benzimidazole compoundshave the formula shown below in formula XXVI:

[0764] or a pharmaceutically acceptable salt thereof, wherein:

[0765] A¹⁰ is heteroaryl selected from a 5-membered monocyclic aromaticring having one hetero atom selected from O, S and N and optionallycontaining one to three N atom(s) in addition to said hetero atom, or a6-membered monocyclic aromatic ring having one N atom and optionallycontaining one to four N atom(s) in addition to said N atom; and saidheteroaryl being connected to the nitrogen atom on the benzimidazolethrough a carbon atom on the heteroaryl ring;

[0766] X²⁰ is independently selected from halo, C₁-C₄ alkyl, hydroxy,C₁C₄ alkoxy, halo-substituted C₁-C₄ alkyl, hydroxy-substituted C₁-C₄alkyl, (C₁-C₄ alkoxy)C₁-C₄ alkyl, halo-substituted C₁-C₄ alkoxy, amino,N-(C₁-C₄ alkyl)amino, N,N-di(C₁-C₄ alkyl)amino, [N-(C₁-C₄alkyl)amino]C₁-C₄ alkyl, [N,N-di(C₁-C₄ alkyl)amino]C₁-C₄ alkyl, N-(C₁-C₄alkanoyl)amonio, N-(C₁-C₄ alkyl)(C₁-C₄ alkanoyl)amino, N-[(C₁-C₄alkyl)sulfonyl]amino, N-[(halo-substituted C₁-C₄ alkyl)sulfonyl]amino,C₁-C₄ alkanoyl, carboxy, (C₁-C₄ alkoxy)carbonyl, carbamoyl, [N-(C₁-C₄alkyl)amino]carbonyl, [N,N-di(C₁-C₄ alkyl)amino]carbonyl, cyano, nitro,mercapto, (C₁-C₄ alkyl)thio, (C₁-C₄ alkyl)sulfinyl, (C₁-C₄alkyl)sulfonyl, aminosulfonyl, [N-(C₁-C₄ alkyl)amino]sulfonyl and[N,N-di(C₁-C₄ alkyl)amino]sulfonyl;

[0767]  X²¹ is independently selected from halo, C₁-C₄ alkyl, hydroxy,C₁-C₄ alkoxy, halo-substituted C₁-C₄ alkyl, hydroxy-substituted C₁-C₄alkyl, (C₁-C₄ alkoxy)C₁-C₄ alkyl, halo-substituted C₁-C₄ alkoxy, amino,N-(C₁-C₄ alkyl)amino, N,N-di(C₁-C₄ alkyl)amino, [N-(C₁-C₄alkyl)amino]c₁-C₄ alkyl, [N,N-di(C₁-C₄ alkyl)amino]C₁-C₄ alkyl, N-(C₁-C₄alkanoyl)amino, N-(C₁-C₄ alkyl)-N-(C₁-C₄ alkanoyl) amino, N-[(C₁-C₄alkyl)sulfonyl]amino, N-[(halo-substituted C₁-C₄ alkyl)sulfonyl]amino,C₁-C₄ alkanoyl, carboxy, (C₁-C₄ alkoxy)cabonyl, cabamoyl, [N-(C₁-C₄alkyl) amino]carbonyl, [N,N-di(C₁-C₄ alkyl)amino]carbonyl,N-carbomoylamino, cyano, nitro, mercapto, (C₁-C₄ alkyl)thio, (C₁-C₄alkyl)sulfinyl, (C₁-C₄ alkyl)sulfonyl, aminosulfonyl, [N-(C₁-C₄alkyl)amino]sulfonyl and [N,N-di(C₁-C₄ alkyl)amino]sulfonyl;

[0768] R¹³⁸ is selected from hydrogen,

[0769] straight or branched C₁-C₄ alkyl optionally substituted with oneto three substituent(s) wherein said substituents are independentlyselected from halo hydroxy, C₁-C₄ alkoxy, amino, N-(C₁-C₄ alkyl)aminoand N,N-di(C₁-C₄ alkyl)amino,

[0770] C₃-C₈ cycloalkyl optionally substituted with one to threesubstituent(s) wherein said substituents are indepently selected fromhalo, C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, amino, N-(C₁-C₄ alkyl)aminoand N, N-di(C₁-C₄ alkyl)amino,

[0771] C₄-C₈ cycloalkenyl optionally substituted with one to threesubstituent(s) wherein said substituents are independently selected fromhalo, C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, amino, N-(C₁-C₄ alkyl)aminoand N,N-di(C₁-C₄ alkyl)amino,

[0772] phenyl optionally substituted with one to three substituent(s)wherein said substituents are independently selected from halo, C₁-C₄alkyl, hydroxy, C₁-C₄ alkoxy, halo-substituted C₁-C₄ alkyl,hydroxy-substituted C₁-C₄ alkyl, (C₁-C₄ alkoxy)C₁-C₄ alkyl,halo-substituted C₁-C₄ alkoxy, amino, N-(C₁-C₄ alkyl)amino, N,N-di(C₁-C₄alkyl)amino, [N-(C₁-C₄ alkyl)amino]C₁-C₄ alkyl, [N,N-di(C₁-C₄alkyl)amino]C₁-C₄ alkyl, N-(C₁-C₄ alkanoyl)amino, N-[C₁-C₄ alkyl)(C₁-C₄alkanoyl)]amino, N-[(C₁-C₄ alkyl)sulfony]amino, N-[(halo-substitutedC₁-C₄ alkyl)sulfonyl]amino, C₁-C₄ alkanoyl, carboxy, (C₁-C₄alkoxy)carbonyl, carbomoyl, [N-(C₁-C₄ alky)amino]carbonyl, [N,N-di(C₁-C₄alkyl)amino]carbonyl, cyano, nitro, mercapto, (C₁-C₄ alkyl)thio, (C₁-C₄alkyl)sulfinyl, (C₁-C₄ alkyl)sulfonyl, aminosulfonyl, [N-(C₁-C₄alkyl)amino]sulfonyl and [N,N-di(C₁-C₄ alkyl)amino]sulfonyl; and

[0773] heteroaryl selected from:

[0774] a 5-membered monocyclic aromatic ring having one hetero atomselected from O, S and N and optionally containing one to three Natom(s) in addition to said hetero atom; or a 6-membered monocyclicaromatic ring having one N atom and optionally containing one to four Natom(s) in addition to said N atom; and

[0775] said heteroaryl being optionally substituted with one to threesubstituent(s) selected from X²⁰;

[0776] R¹³⁹ and R¹⁴⁰ are independently selected from:

[0777] hydrogen,

[0778] halo,

[0779] C₁-C₄ alkyl,

[0780] phenyl optionally substituted with one to three substituent(s)wherein said substituents are independently selected from halo, C₁-C₄alkyl, hydroxy, C₁-C₄ alkoxy, amino, N-(C₁-C₄ alkyl)amino andN,N-di(C₁-C₄ alkyl)amino,

[0781] or R¹³⁸ and R¹³⁹ can form, together with the carbon atom to whichthey are attached, a C₃-C₇ cycloalkyl ring;

[0782] m is 0, 1, 2, 3, 4 or 5; and

[0783] n is 0, 1, 2, 3 or 4.

[0784] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include indole compounds that aredescribed in U.S. Pat. No. 6,300,363. Such indole compounds have theformula shown below in formula XXVII:

[0785] and the pharmaceutically acceptable salts thereof,

[0786] wherein:

[0787] L⁴ is oxygen or sulfur;

[0788] Y³ is a direct bond or C₁₋₄ alkylidene;

[0789] Q⁶ is:

[0790] (a) C₁₋₆ alkyl or halosubstituted C₁₋₆ alkyl, said alkyl beingoptionally substituted with up to three substituents independentlyselected from hydroxy, C₁₋₄ alkoxy, amino and mono- or di-(C₁₋₄alkyl)amino,

[0791] (b) C₃₋₇ cycloalkyl optionally substituted with up to threesubstituents independently selected from hydroxy, C₁₋₄ alkyl and C₁₋₄alkoxy,

[0792] (c) phenyl or naphthyl, said phenyl or naphthyl being optionallysubstituted with up to four substituents independently selected from:(c-1) halo, C₁₋₄ alkyl, halosubstituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halosubstituted C₁₋₄ alkoxy, S(O)_(m) R¹⁴³, SO₂ NH₂, SO₂ N(C₁₋₄alkyl)₂, amino, mono- or di-(C₁₋₄ alkyl)amino, NHSO₂ R¹⁴³, NHC(O)R¹⁴³,CN, CO₂H, CO₂ (C₁₋₄ alkyl), C₁₋₄ alkyl-OH, C₁₋₄ alkyl-OR¹⁴³, CONH₂,CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂ and —O—Y-phenyl, said phenyl beingoptionally substituted with one or two substituents independentlyselected from halo, C₁₋₄ alkyl, CF₃, hydroxy, OR¹⁴³, S(O)_(m)R¹⁴³,amino, mono- or di-(C₁₋₄ alkyl)amino and CN;

[0793] (d) a monocyclic aromatic group of 5 atoms, said aromatic grouphaving one heteroatom selected from O, S and N and optionally containingup to three N atoms in addition to said heteroatom, and said aromaticgroup being substituted with up to three substitutents independentlyselected from:

[0794] (d-1) halo, C₁₋₄ alkyl, halosubstituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halosubstituted C₁₋₄ alkoxy, C₁₋₄ alkyl-OH, S(O)_(m) R⁴³, SO₂NH₂, SO₂ N(C₁₋₄ alkyl)₂, amino, mono- or di-(C₁₋₄ alkyl)amino, NHSO₂R¹⁴³, NHC(O)R¹⁴³ CN, CO₂H, CO₂ (C₁₋₄ alkyl), C₁₋₄ alkyl-OR⁴³, CONH₂,CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, phenyl, and mono-, di- ortri-substituted phenyl wherein the substituent is independently selectedfrom halo, CF₃, C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, OCF₃, SR¹⁴³, SO₂ CH₃,SO₂ NH₂, amino, C₁₋₄ alkylamino and NHSO₂ R¹⁴³;

[0795] (e) a monocyclic aromatic group of 6 atoms, said aromatic grouphaving one heteroatom which is N and optionally containing up to threeatoms in addition to said heteroatom, and said aromatic group beingsubstituted with up to three substituents independently selected fromthe above group (d-1);

[0796] R¹⁴¹ is hydrogen or C₁₋₆ alkyl optionally substituted with asubstituent selected independently from hydroxy, OR¹⁴³, nitro, amino,mono- or di-(C₁₋₄ alkyl)amino, CO₂H, CO₂ (C₁₋₄ alkyl), CONH₂, CONH(CO₁₄alkyl) and CON(CO₁₄ alkyl)₂;

[0797] R¹⁴² is:

[0798] (a) hydrogen,

[0799] (b) C₁₋₄ alkyl,

[0800] (c) C(O)R¹⁴⁵,

[0801]  wherein R¹⁴⁵ is selected from:

[0802] (c-1) C₁₋₂₂ alkyl or C₂₋₂₂ alkenyl, said alkyl or alkenyl beingoptionally substituted with up to four substituents independentlyselected from: (c-1-1) halo, hydroxy, OR¹⁴³, S(O)_(m) R¹⁴³, nitro,amino, mono- or di-(C₁₋₄ alkyl)amino, NHSO₂ R¹⁴³, CO₂H, CO₂ (C₁₋₄alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, OC(O)R¹⁴³, thienyl,naphthyl and groups of the following formulae:

[0803] (c-2) C₁₋₂₂ alkyl or C₂₋₂₂ alkenyl, said alkyl or alkenyl beingoptionally substituted with five to forty-five halogen atoms,

[0804] (c-3) —Y⁵—C₃₋₇ cycloalkyl or —Y⁵—C₃₋₇ cycloalkenyl, saidcycloalkyl or cycloalkenyl being optionally substituted with up to threesubstituent independently selected from:

[0805]  (c-3-1) C₁₋₄ alkyl, hydroxy, OR¹⁴³, S(O)_(m) R¹⁴³, amino, mono-or di-(C₁₋₄ alkyl)amino, CONH₂, CONH(C₁₋₄ alkyl) and CON(C₁₋₄ alkyl)₂,(c-4) phenyl or naphthyl, said phenyl or naphthyl being optionallysubstituted with up to seven (preferably up to seven) substituentsindependently selected from:

[0806]  (c-4-1) halo, C₁₋₈ alkyl, C₁₋₄ alkyl-OH, hydroxy, C₁₋₈ alkoxy,halosubstituted C₁₋₈ alkyl, halosubstituted C₁₋₈ alkoxy, CN, nitro,S(O)_(m) R⁴³, SO₂ NH₂, SO₂ NH(C₁₋₄ alkyl), SO₂ N(C₁₋₄ alkyl)₂, amino,C₁₋₄ alkylamino, di-(C₁₋₄ alkyl)amino, CONH₂, CONH(CO₁₄ alkyl), CON(CO₁₄alkyl)₂, OC(O)R¹⁴³, and phenyl optionally substituted with up to threesubstituents independently selected from halo, C₁₋₁₄ alkyl, hydroxy,OCH₃, CF₃, OCF₃, CN, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, CO₂H,CO₂ (C₁₋₄ alkyl) and CONH₂,

[0807] (c-5) a monocyclic aromatic group as defined in (d) and (e)above, said aromatic group being optionally substituted with up to threesubstituents independently selected from:

[0808]  (c-5-1) halo, C₁₋₈ alkyl, C₁₋₄ alkyl-OH, hydroxy, C₁₋₈ alkoxy,CF₃, OCF₃, CN, nitro, S(O)_(m) R¹⁴³, amino, mono- or di-(C₁₋₄alkyl)amino, CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, CO₂H and CO₂(C₁₋₄ alkyl), and —Y-phenyl, said phenyl being optionally substitutedwith up to three substituents independently selected halogen, C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, CF₃, OCF₃, CN, nitro, S(O)_(m) R¹⁴³, amino,mono- or di-(C₁₋₄ alkyl)amino, CO₂H, CO₂ (C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄alkyl) and CON(C₁₋₄ alkyl)₂,

[0809] (c-6) a group of the following formula:

[0810] X²² is halo, C₁₋₄ alkyl, hydroxy, C₁₋₁₄ alkoxy, halosubstitutuedC₁₋₄ alkoxy, S(O)_(m) R¹⁴³, amino, mono- or di-(C₁₋₄ alkyl)amino, NHSO₂R¹⁴³, nitro, halosubstitutued C₁₋₄ alkyl, CN, CO₂H, CO₂ (C₁₋₄ alkyl),C₁₋₄ alkyl-OH, C₁₋₄ alkylOR¹⁴³, CONH₂, CONH(C₁₋₄ alkyl) or CON(C₁₋₄alkyl)₂; R¹⁴³ is C₁₋₄ alkyl or halosubstituted C₁₋₄ alkyl;

[0811] m is 0, 1 or 2; n is 0, 1, 2 or 3; p is 1, 2, 3, 4 or 5; q is 2or 3; Z¹¹ is oxygen, sulfur or NR¹⁴⁴; and

[0812] R¹⁴⁴ is hydrogen, C₁₋₆ alkyl, halosubstitutued C₁₋₄ alkyl or—Y⁵-phenyl, said phenyl being optionally substituted with up to twosubstituents independently selected from halo, C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, S(O)_(m) R¹⁴³, amino, mono- or di-(C₁₋₄ alkyl)amino, CF₃, OCF₃,CN and nitro;

[0813] with the proviso that a group of formula —Y⁵-Q is not methyl orethyl when X²² is hydrogen;

[0814] L⁴ is oxygen;

[0815] R¹⁴¹ is hydrogen; and

[0816] R¹⁴² is acetyl.

[0817] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include aryl phenylhydrazides thatare described in U.S. Pat. No. 6,077,869. Such aryl phenylhydrazideshave the formula shown below in formula XXVIII:

[0818] wherein:

[0819] X²³ and Y⁶ are selected from hydrogen, halogen, alkyl, nitro,amino or other oxygen and sulfur containing functional groups such ashydroxy, methoxy and methylsulfonyl.

[0820] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include 2-aryloxy, 4-arylfuran-2-ones that are described in U.S. Pat. No. 6,140,515. Such2-aryloxy, 4-aryl furan-2-ones have the formula shown below in formulaXXIX:

[0821] or a pharmaceutical salt thereof,

[0822] wherein:

[0823] R¹⁴⁶ is selected from the group consisting of SCH₃, —S(O)₂ CH₃and —S(O)₂ NH₂;

[0824] R¹⁴⁷ is selected from the group consisting of OR¹⁵⁰, mono ordi-substituted phenyl or pyridyl wherein the substituents are selectedfrom the group consisting of methyl, chloro and F;

[0825] R¹⁵⁰ is unsubstituted or mono or di-substituted phenyl or pyridylwherein the substituents are selected from the group consisting ofmethyl, chloro and F;

[0826] R¹⁴⁸ is H, C₁₋₄ alkyl optionally substituted with 1 to 3 groupsof F, Cl or Br; and

[0827] R¹⁴⁹ is H, C₁₋₄ alkyl optionally substituted with 1 to 3 groupsof F, Cl or Br, with the proviso that R¹⁴⁸ and R¹⁴⁹ are not the same.

[0828] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include bisaryl compounds that aredescribed in U.S. Pat. No. 5,994,379. Such bisaryl compounds have theformula shown below in formula XXX:

[0829] or a pharmaceutically acceptable salt, ester or tautomer thereof,

[0830] wherein:

[0831] Z¹³ is Cor N;

[0832]  when Z¹³ is N, R¹⁵¹ represents H or is absent, or is taken inconjunction with R¹⁵² as described below:

[0833] when Z¹³ is C, R¹⁵¹ represents H and R¹⁵² is a moiety which hasthe following characteristics:

[0834] (a) it is a linear chain of 3-4 atoms containing 0-2 doublebonds, which can adopt an energetically stable transoid configurationand if a double bond is present, the bond is in the trans configuration,

[0835] (b) it is lipophilic except for the atom bonded directly to ringA, which is either lipophilic or non-lipophilic, and

[0836] (c) there exists an energetically stable configuration planarwith ring A to within about 15 degrees;

[0837] or R¹⁵¹ and R¹⁵² are taken in combination and represent a 5- or6-membered aromatic or non-aromatic ring D fused to ring A, said ring Dcontaining 0-3 heteroatoms selected from O, S and N;

[0838] said ring D being lipophilic except for the atoms attacheddirectly to ring A, which are lipophilic or non-lipophilic, and saidring D having available an energetically stable configuration planarwith ring A to within about 15 degrees;

[0839] said ring D further being substituted with 1 Ra group selectedfrom the group consisting of: C₁₋₂ alkyl, —OC₁₋₂ alkyl, —NHC₁₋₂ alkyl,—N(C₁₋₂ alkyl)₂, —C(O)C₁₋₂ alkyl, —S—C₁₋₂ alkyl and —C(S)C₁₋₂ alkyl;

[0840] Y⁷ represents N, CH or C—OC₁₋₃ alkyl, and when Z¹³ is N, Y⁷ canalso represent a carbonyl group;

[0841] R¹⁵³ represents H, Br, Cl or F; and

[0842] R¹⁵⁴ represents H or CH₃.

[0843] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include 1,5-diarylpyrazoles that aredescribed in U.S. Pat. No. 6,028,202. Such 1,5-diarylpyrazoles have theformula shown below in formula X)XI:

[0844] wherein:

[0845] R¹⁵⁵, R¹⁵⁶, R¹⁵⁷, and R¹⁵⁸ are independently selected from thegroups consisting of hydrogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, phenyl, halo,hydroxy, C₁₋₅ alkylsulfonyl, C₁₋₅ alkylthio, trihaloC₁₋₅ alkyl, amino,nitro and 2-quinolinylmethoxy;

[0846] R¹⁵⁹ is hydrogen, C₁₋₅ alkyl, trihaloC₁₋₅ alkyl, phenyl,substituted phenyl where the phenyl substitutents are halogen, C₁₋₅alkoxy, trihaloC₁₋₅ alkyl or nitro or R¹⁵⁹ is heteroaryl of 5-7 ringmembers where at least one of the ring members is nitrogen, sulfur oroxygen;

[0847] R¹⁶⁰ is hydrogen, C₁₋₅ alkyl, phenyl C₁₋₅ alkyl, substitutedphenyl C₁₋₅ alkyl where the phenyl substitutents are halogen, C₁₋₅alkoxy, trihaloC₁₋₅ alkyl or nitro, or R¹⁶⁰ is C₁₋₅ alkoxycarbonyl,phenoxycarbonyl, substituted phenoxycarbonyl where the phenylsubstitutents are halogen, C₁₋₅ alkoxy, trihaloC₁₋₅ alkyl or nitro;

[0848] R¹⁶¹ is C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl where thesubstituents are halogen, trihaloC₁₋₅ alkyl, C₁₋₅ alkoxy, carboxy, C₁₋₅alkoxycarbonyl, amino, C₁₋₅ alkylamino, diC₁₋₅ alkylamino, diC₁₋₅alkylaminoC₁₋₅ alkylamino, C₁₋₅ alkylaminoC₁₋₅ alkylamino or aheterocycle containing 4-8 ring atoms where one more of the ring atomsis nitrogen, oxygen or sulfur, where said heterocycle may be optionallysubstituted with C₁₋₅ alkyl; or R¹⁶¹ is phenyl, substituted phenyl(where the phenyl substitutents are one or more of C₁₋₅ alkyl, halogen,C₁₋₅ alkoxy, trihaloC₁₋₅ alkyl or nitro), or R¹⁶¹ is heteroaryl having5-7 ring atoms where one or more atoms are nitrogen, oxygen or sulfur,fused heteroaryl where one or more 5-7 membered aromatic rings are fusedto the heteroaryl; or

[0849] R¹⁶¹ is NR¹⁶³ R¹⁶⁴ where R¹⁶³ and R¹⁶⁴ are independently selectedfrom hydrogen and C₁₋₅ alkyl or R¹⁶³ and R¹⁶⁴ may be taken together withthe depicted nitrogen to form a heteroaryl ring of 5-7 ring memberswhere one or more of the ring members is nitrogen, sulfur or oxygenwhere said heteroaryl ring may be optionally substituted with C₁₋₅alkyl;

[0850] R¹⁶² is hydrogen, C₁₋₅ alkyl, nitro, amino, and halogen;

[0851] and pharmaceutically acceptable salts thereof.

[0852] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include 2-substituted imidazoles thatare described in U.S. Pat. No. 6,040,320. Such 2-substituted imidazoleshave the formula shown below in formula XXXII:

[0853] wherein:

[0854] R¹⁶⁴ is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6ring atoms, or

[0855] substituted phenyl;

[0856] wherein the substituents are independently selected from one ormembers of the group consisting of C₁₋₅ alkyl, halogen, nitro,trifluoromethyl and nitrile;

[0857] R¹⁶⁵ is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6ring atoms,

[0858] substituted heteroaryl;

[0859] wherein the substituents are independently selected from one ormore members of the group consisting of C₁₋₅ alkyl and halogen, orsubstituted phenyl,

[0860] wherein the substituents are independently selected from one ormembers of the group consisting of C₁₋₅ alkyl, halogen, nitro,trifluoromethyl and nitrile;

[0861] R¹⁶⁶ is hydrogen, SEM, C₁₋₅ alkoxycarbonyl, aryloxycarbonyl,arylC₁₋₅ alkyloxycarbonyl, arylC₁₋₅ alkyl, phthalimidoC₁₋₅ alkyl,aminoC₁₋₅ alkyl, diaminoC₁₋₅ alkyl, succinimidoC₁₋₅ alkyl, C₁₋₅alkylcarbonyl, arylcarbonyl, C₁₋₅ alkylcarbonylC₁₋₅ alkyl,aryloxycarbonylC₁₋₅ alkyl, heteroarylC₁₋₅ alkyl where the heteroarylcontains 5 to 6 ring atoms, or substituted arylC₁₋₅ alkyl,

[0862] wherein the aryl substituents are independently selected from oneor more members of the group consisting of C₁₋₅ alkyl, C₁₋₅ alkoxy,halogen, amino, C₁₋₅ alkylamino, and diC₁₋₅ alkylamino;

[0863] R¹⁶⁷ is (A¹¹)_(n)—(CH¹⁶⁵)_(q)—X²⁴ wherein:

[0864] A¹¹ is sulfur or carbonyl;

[0865] n is 0 or 1;

[0866] q is 0-9;

[0867] X²⁴ is selected from the group consisting of hydrogen, hydroxy,halogen, vinyl, ethynyl, C₁₋₅ alkyl, C₃₋₇ cycloalkyl, C₁₋₅ alkoxy,phenoxy, phenyl, arylC₁₋₅ alkyl, amino, C₁₋₅ alkylamino, nitrile,phthalimido, amido, phenylcarbonyl, C₁₋₅ alkylaminocarbonyl,phenylaminocarbonyl, arylC₁₋₅ alkylaminocarbonyl, C₁₋₅ alkylthio, C₁₋₅alkylsulfonyl, phenylsulfonyl,

[0868] substituted sulfonamido,

[0869] wherein the sulfonyl substituent is selected from the groupconsisting of C₁₋₅ alkyl, phenyl, araC₁₋₅ alkyl, thienyl, furanyl, andnaphthyl;

[0870] substituted vinyl,

[0871] wherein the substituents are independently selected from one ormembers of the group consisting of fluorine, bromine, chlorine andiodine,

[0872] substituted ethynyl,

[0873] wherein the substituents are independently selected from one ormore members of the group consisting of fluorine, bromine chlorine andiodine,

[0874] substituted C₁₋₅ alkyl,

[0875] wherein the substituents are selected from the group consistingof one or more C₁₋₅ alkoxy, trihaloalkyl, phthalimido and amino,

[0876] substituted phenyl,

[0877] wherein the phenyl substituents are independently selected fromone or more members of the group consisting of C₁₋₅ alkyl, halogen andC₁₋₅ alkoxy,

[0878] substituted phenoxy,

[0879] wherein the phenyl substituents are independently selected fromone or more members of the group consisting of C₁₋₅ alkyl, halogen andC₁₋₅ alkoxy,

[0880] substituted C₁₋₅ alkoxy,

[0881]  wherein the alkyl substituent is selected from the groupconsisting of phthalimido and amino,

[0882] substituted arylC₁₋₅ alkyl,

[0883] wherein the alkyl substituent is hydroxyl,

[0884] substituted arylC₁₋₅ alkyl,

[0885] wherein the phenyl substituents are independently selected fromone or more members of the group consisting of C₁₋₅ alkyl, halogen andC₁₋₅ alkoxy,

[0886] substituted amido,

[0887] wherein the carbonyl substituent is selected from the groupconsisting of C₁₋₅ alkyl, phenyl, arylC₁₋₅ alkyl, thienyl, furanyl, andnaphthyl, substituted phenylcarbonyl,

[0888] wherein the phenyl substituents are independently selected fromone or members of the group consisting of C₁₋₅ alkyl, halogen and C₁₋₅alkoxy,

[0889] substituted C₁₋₅ alkylthio,

[0890] wherein the alkyl substituent is selected from the groupconsisting of hydroxy and phthalimido,

[0891] substituted C₁₋₅ alkylsulfonyl,

[0892] wherein the alkyl substituent is selected from the groupconsisting of hydroxy and phthalimido,

[0893] substituted phenylsulfonyl,

[0894] wherein the phenyl substituents are independently selected fromone or members of the group consisting of bromine, fluorine, chlorine,C₁₋₅ alkoxy and trifluoromethyl,

[0895] with the proviso:

[0896] if A¹¹ is sulfur and X²⁴ is other than hydrogen, C₁₋₅alkylaminocarbonyl, phenylaminocarbonyl, arylC₁₋₅ alkylaminocarbonyl,C₁₋₅ alkylsulfonyl or phenylsulfonyl, then q must be equal to or greaterthan 1;

[0897] if A¹¹ is sulfur and q is 1, then X²⁴ cannot be C₁₋₂ alkyl;

[0898] if A¹¹ is carbonyl and q is 0, then X²⁴ cannot be vinyl, ethynyl,C₁₋₅ alkylaminocarbonyl, phenylaminocarbonyl, arylC₁₋₅alkylaminocarbonyl, C₁₋₅ alkylsulfonyl or phenylsulfonyl;

[0899] if A¹¹ is carbonyl, q is 0 and X²⁴ is H, then R¹⁶⁶ is not SEM(2-(trimethylsilyl)ethoxymethyl);

[0900] if n is 0 and q is 0, then X²⁴ cannot be hydrogen;

[0901] and pharmaceutically acceptable salts thereof.

[0902] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include 1,3- and2,3-diarylcycloalkano and cycloalkeno pyrazoles that are described inU.S. Pat. No. 6,083,969. Such 1,3- and 2,3-diarylpyrazole compounds havethe general formulas shown below in formulas XXXIII and XXXIV:

[0903] wherein:

[0904] R¹⁶⁸ and R¹⁶⁹ are independently selected from the groupconsisting of hydrogen, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro,amino, hydroxy, trifluoro, —S(C₁-C₆)alkyl, —SO(C₁-C₆)alkyl and —SO₂(C₁-C₆)alkyl; and the fused moiety M is a group selected from the groupconsisting of an optionally substituted cyclohexyl and cycloheptyl grouphaving the formulae:

[0905] wherein:

[0906] R¹⁷⁰ is selected from the group consisting of hydrogen, halogen,hydroxy and carbonyl;

[0907] or R¹⁷⁰ and R¹⁷¹ taken together form a moiety selected from thegroup consisting of —OCOCH₂—, —ONH(CH₃)COCH₂—, —OCOCH.dbd. and —O—

[0908] R¹⁷¹ and R¹⁷² are independently selected from the groupconsisting of hydrogen, halogen, hydroxy, carbonyl, amino, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, ═NOH, —NR¹⁷⁴ R¹⁷⁵, —OCH₃, —OCH₂ CH₃, —OSO₂ NHCO₂ CH₃,═CHCO₂ CH₂ CH₃, —CH₂ CO₂H, —CH₂ CO₂ CH₃, —CH₂ CO₂ CH₂ CH₃, —CH₂CON(CH₃)₂, —CH₂ CO₂ NHCH₃, —CHCHCO₂ CH₂ CH₃, —OCON(CH₃)OH, —C(COCH₃)₂,di(C₁-C₆)alkyl and di(C₁-C₆)alkoxy;

[0909] R¹⁷³ is selected from the group consisting of hydrogen, halogen,hydroxy, carbonyl, amino, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and optionallysubstituted carboxyphenyl, wherein substituents on the carboxyphenylgroup are selected from the group consisting of halogen, hydroxy, amino,(C₁-C₆)alkyl and (C₁-C₆)alkoxy;

[0910] or R¹⁷² and R¹⁷³ taken together form a moiety selected from thegroup consisting of —O— and

[0911] R¹⁷⁴ is selected from the group consisting of hydrogen, OH,—OCOCH₃, —COCH₃ and (C₁-C₆)alkyl; and

[0912] R¹⁷⁵ is selected from the group consisting of hydrogen, OH,—OCOCH₃, —COCH₃, (C₁-C₆)alkyl, —CONH₂ and —SO₂ CH₃; with the provisothat

[0913] if M is a cyclohexyl group, then R¹⁷⁰ through R¹⁷³ may not all behydrogen; and

[0914] pharmaceutically acceptable salts, esters and pro-drug formsthereof.

[0915] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include esters derived fromindolealkanois and novel amides derived from indolealkylamides that aredescribed in U.S. Pat. No. 6,306,890. Such compounds have the generalformula shown below in formula XXXV:

[0916] wherein:

[0917] R¹⁷⁶ is C₁ to C₆ alkyl, C₁ to C₆ branched alkyl, C₄ to C₈cycloalkyl, C₁ to C₆ hydroxyalkyl, branched C₁ to C₆ hydroxyalkyl,hydroxy substituted C₄ to C₈ aryl, primary, secondary or tertiary C, toC₆ alkylamino, primary, secondary or tertiary branched C₁ to C₆alkylamino, primary, secondary or tertiary C₄ to C₈ arylamino, C₁ to C₆alkylcarboxylic acid, branched C₁ to C₆ alkylcarboxylic acid, C₁ to C₆alkylester, branched C₁ to C₆ alkylester, C₄ to C₈ aryl, C₄ to C₈arylcarboxylic acid, C₄ to C₈ arylester, C₄ to C₈ aryl substituted C₁ toC₆ alkyl, C₄ to C₈ heterocyclic alkyl or aryl with O, N or S in thering, alkyl-substituted or aryl-substituted C₄ to C₈ heterocyclic alkylor aryl with O, N or S in the ring, or halo-substituted versionsthereof, where halo is chloro, bromo, fluoro or iodo;

[0918] R¹⁷⁷ is C₁ to C₆ alkyl, C₁ to C₆ branched alkyl, C₄ to C₈cycloalkyl, C₄ to C₈ aryl, C₄ to C₈ aryl-substituted C₁ to C₆ alkyl, C₁to C₆ alkoxy, C₁ to C₆ branched alkoxy, C₄ to C₈ aryloxy, orhalo-substituted versions thereof or R¹⁷⁷ is halo where halo is chloro,fluoro, bromo, or iodo;

[0919] R¹⁷⁸ is hydrogen, C₁ to C₆ alkyl or C, to C₆ branched alkyl;

[0920] R¹⁷⁹ is C₁ to C₆ alkyl, C₄ to C₈ aroyl, C₄ to C₈ aryl, C₄ to C₈heterocyclic alkyl or aryl with O, N or S in the ring, C₄ to C₈aryl-substituted C₁ to C₆ alkyl, alkyl-substituted or aryl-substitutedC₄ to C₈ heterocyclic alkyl or aryl with O, N or S in the ring,alkyl-substituted C₄ to C₈ aroyl, or alkyl-substituted C₄ to C₈ aryl, orhalo-substituted versions thereof where halo is chloro, bromo, or iodo;

[0921] n is 1, 2, 3, or 4; and

[0922] X²⁵ is O, NH, or N—R¹⁸⁰, where R¹⁸⁰ is C₁ to C₆ alkyl or C, to C₆branched alkyl.

[0923] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include pyridazinone compounds thatare described in U.S. Pat. No. 6,307,047. Such pyridazinone compoundshave the formula shown below in formula XXXVI:

[0924] or a pharmaceutically acceptable salt, ester, or prodrug thereof,

[0925] wherein:

[0926] X²⁶ is selected from the group consisting of O, S, —NR¹⁸⁵,—NOR^(a), and —NNR^(b) R^(c);

[0927] R¹⁸⁵ is selected from the group consisting of alkenyl, alkyl,aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;

[0928] R^(a), R^(b), and R^(c) are independently selected from the groupconsisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;

[0929] R¹⁸¹ is selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl,alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl,arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl,aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl,cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl,haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl,heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, —(CH₂)_(n) C(O)R¹⁸⁶,—(CH₂)_(n) CH(OH)R¹⁸⁶, —(CH₂)_(n) C(NORd)R¹⁸⁶, —(CH₂)_(n) CH(NORd)R¹⁸⁶,—(CH₂)_(n) CH(NRd Re)R¹⁸⁶, —R¹⁸⁷ R¹⁸⁸, —(CH₂)_(n) C□CR¹⁸⁸, —(CH₂)_(n)[CH(CX^(26′) ₃)]_(m) (CH₂)_(p) R¹⁸⁸, —(CH₂)_(n) (CX²⁶ ^(₁) ₂)_(m)(CH₂)_(p) R¹⁸⁸, and —(CH₂)_(n) (CHX²⁶ ^(₁) ) (CH₂)_(m) R¹⁸⁸;

[0930] R¹⁸⁶ is selected from the group consisting of hydrogen, alkenyl,alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl,haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;

[0931] R¹⁸⁷ is selected from the group consisting of alkenylene,alkylene, halo-substituted alkenylene, and halo-substituted alkylene;

[0932] R¹⁸⁸ is selected from the group consisting of hydrogen, alkenyl,alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl,heterocyclic, and heterocyclic alkyl;

[0933] R^(d) and R^(e) are independently selected from the groupconsisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl,cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclicalkyl;

[0934] X^(26′) is halogen;

[0935] m is an integer from 0-5;

[0936] n is an integer from 0-10; and

[0937] p is an integer from 0-10; and

[0938] R¹⁸², R¹⁸³, and R¹⁸⁴ are independently selected from the groupconsisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy,alkoxyiminoalkyl, alkyl, alkynyl, alkylcarbonylalkoxy,alkylcarbonylamino, alkylcarbonylaminoalkyl, aminoalkoxy,aminoalkylcarbonyloxyalkoxy aminocarbonylalkyl, aryl, arylalkenyl,arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano,cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, haloalkenyloxy,haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy,hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, nitro,phosphonatoalkoxy, Y⁸, and Z¹⁴;

[0939] provided that one of R¹⁸², R¹⁸³ or R¹⁸⁴ must be Z¹⁴, and furtherprovided that only one of R¹⁸², R¹⁸³, or R¹⁸⁴ is Z¹⁴;

[0940] Z¹⁴ is selected from the group consisting of:

[0941]²⁷ is selected from the group consisting of S(O)₂, S(O)(NR¹⁹¹),S(O), Se(O)₂, P(O)(OR¹⁹²), and P(O)(NR¹⁹³ R¹⁹⁴);

[0942] X²⁸ is selected from the group consisting of hydrogen, alkenyl,alkyl, alkynyl and halogen;

[0943] R¹⁹⁰ is selected from the group consisting of alkenyl, alkoxy,alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl,cycloalkyl, dialkylamino, —NHNH₂, and —NCHN(R¹⁹¹)R¹⁹²;

[0944] R¹⁹¹, R¹⁹², R¹⁹³, and R¹⁹⁴ are independently selected from thegroup consisting of hydrogen, alkyl, and cycloalkyl, or R¹⁹³ and R¹⁹⁴can be taken together, with the nitrogen to which they are attached, toform a 3-6 membered ring containing 1 or 2 heteroatoms selected from thegroup consisting of O, S, and NR¹⁸⁸;

[0945] Y⁸ is selected from the group consisting of —OR¹⁹⁵, —SR¹⁹⁵,—C(R¹⁹⁷)(R¹⁹⁸)R¹⁹⁵, —C(O)R¹⁹⁵, —C(O)OR¹⁹⁵, —N(R¹⁹⁷)C(O)R¹⁹⁵,—NC(R¹⁹⁷)R¹⁹⁵, and —N(R¹⁹⁷)R¹⁹⁵;

[0946] R¹⁹⁵ is selected from the group consisting of hydrogen, alkenyl,alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl,cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocyclic, heterocyclic alkyl, hydroxyalkyl, and NR¹⁹⁹ R²⁰⁰; and

[0947] R¹⁹⁷, R¹⁹⁸, R¹⁹⁹, and R²⁰⁰ are independently selected from thegroup consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl,cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl.

[0948] Materials that can serve as a cyclooxygenase-2 selectiveinhibitor of the present invention include benzosulphonamide derivativesthat are described in U.S. Pat. No. 6,004,948. Such benzosulphonamidederivatives have the formula shown below in formula XXXVII:

[0949] herein:

[0950] A¹² denotes oxygen, sulphur or NH;

[0951] R²⁰¹ denotes a cycloalkyl, aryl or heteroaryl group optionallymono- or polysubstituted by halogen, alkyl, CF₃ or alkoxy;

[0952] D⁵ denotes a group of formula XXXVIII or XXXIX:

[0953] R²⁰² and R²⁰³ independently of each other denote hydrogen, anoptionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroarylradical or a radical (CH₂)_(n)—X²⁹; or

[0954] R²⁰² and R²⁰³ together with the N-atom denote a three- toseven-membered, saturated, partially or totally unsaturated heterocyclewith one or more heteroatoms N, O, or S, which may optionally besubstituted by oxo, an alkyl, alkylaryl or aryl group or a group(CH₂)_(n)—X²⁹, R²⁰²′ denotes hydrogen, an optionally polyfluorinatedalkyl group, an aralkyl, aryl or heteroaryl group or a group(CH₂)_(n)—X²⁹,

[0955] wherein:

[0956] X²⁹ denotes halogen, NO₂, —OR²⁰⁴, —COR²⁰⁴, —CO₂ R²⁰⁴, —OCO₂ R,—CN, —CONR²⁰⁴ OR²⁰⁵-CONR²⁰⁴ R²⁰⁵, —SR²⁰⁴ S(O)R²⁰⁴, —S(O)₂ R²⁰⁴, —NR²⁰⁴R²⁰⁵, —NHC(O)R²⁰⁴, —NHS(O)₂ R²⁰⁴; Z¹⁵ denotes —CH₂—, —CH₂—CH₂—,—CH₂—CH₂—CH₂—, —CH₂—CH═CH—, —CH═CH—CH₂—, —CH₂—CO—, —CO—CH₂—, —NHCO—,—CONH—, —NHCH₂—, —CH₂ NH—, —N═CH—, —NHCH—, —CH₂—CH₂—NH—, —CH═CH—,>N—R²⁰³, >C═O, >S(O)_(m);

[0957] R²⁰⁴ and R²⁰⁵ independently of each other denote hydrogen, alkyl,aralkyl or aryl;

[0958] n is an integer from 0 to 6;

[0959] R²⁰⁶ is a straight-chained or branched C₁₋₄-alkyl group which mayoptionally be mono- or polysubstituted by halogen or alkoxy, or R²⁰⁶denotes CF₃; and

[0960] m denotes an integer from 0 to 2;

[0961] with the proviso that A¹² does not represent 0 if R²⁰⁶ denotesCF₃;

[0962] and the pharmaceutically acceptable salts thereof.

[0963] Cox-2 selective inhibitors that are useful in the subject methodand compositions can include the compounds that are described in U.S.Pat. Nos. 6,169,188, 6,020,343, 5,981,576 ((methylsulfonyl)phenylfuranones); U.S. Pat. No. 6,222,048 (diaryl-2-(5H)-furanones); U.S. Pat.No. 6,057,319 (3,4-diaryl-2-hydroxy-2,5-dihydrofurans); U.S. Pat. No.6,046,236 (carbocyclic sulfonamides); U.S. Pat. Nos. 6,002,014 and5,945,539 (oxazole derivatives); and U.S. Pat. No. 6,359,182 (C-nitrosocompounds).

[0964] Cyclooxygenase-2 selective inhibitors that are useful in thepresent invention can be supplied by any source as long as thecyclooxygenase-2-selective inhibitor is pharmaceutically acceptable.Cyclooxygenase-2-selective inhibitors can be isolated and purified fromnatural sources or can be synthesized. Cyclooxygenase-2-selectiveinhibitors should be of a quality and purity that is conventional in thetrade for use in pharmaceutical products.

[0965] Another component of the present invention is a colds and coughactive ingredient. It is preferred that the colds and cough activeingredient is different than the cyclooxygenase-2 selective inhibitor.In general, colds and cough medications can be used to relieve the coughand other symptoms due to colds, influenza, or hay fever. Commonly, twoor more ingredients that have activity against the same or differentsymptoms of colds or coughs can be used together in a combination. Asthese terms are used herein, “colds and cough active ingredient” ismeant to include any element, compound or material, alone or incombination, that has been used for, or has been shown to be useful for,the prevention, treatment or amelioration of at least one symptomcommonly associated with colds or cough. Examples of general categoriesof colds and cough active ingredients include antihistamines,decongestants, antitussives, expectorants, analgesics, anticholinergicsand antiviral agents. It should be understood that when any colds andcough active ingredient is referred to herein, all pharmaceuticallyacceptable salts and prodrugs of the material are also included unlessspecified otherwise.

[0966] Antihistamines are used to relieve or prevent the symptoms of hayfever and other types of allergy. They also help relieve some symptomsof the common cold, such as sneezing and runny nose. They work bypreventing the effects of histamine, which is produced by the body. Someexamples of antihistamines are: bromodiphenhydramine, brompheniramine,carbinoxamine, chlorpheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, phenindamine, pheniramine, phenyltoloxamine, pyrilamine,promethazine, triprolidine, loratadine, and cetirzine.

[0967] Decongestants, such as ephedrine, phenylephrine,phenylpropanolamine and pseudoephedrine, produce a narrowing of bloodvessels. This leads to clearing of nasal congestion.

[0968] Antitussives help relieve coughing. Examples of antitussivesinclude those which are narcotics, such as codeine, dihydrocodeine,hydrocodone and hydromorphone, or a non-narcotic, such ascarbetapentane, caramiphen, or dextromethorphan. It is believed thatantitussives act directly on the cough center in the brain.

[0969] Expectorants, such as guaifenesin, are believed to work byloosening the mucus or phlegm in the lungs. Examples of otheringredients that are added as expectorants include ammonium chloride,calcium iodide, iodinated glycerol, ipecac, potassium guaiacolsulfonate,potassium iodide, and sodium citrate.

[0970] Analgesics, such as acetaminophen, aspirin, and othersalicylates, such as salicylamide and sodium salicylate, are used tohelp relieve the aches and pain that may occur with the common cold.

[0971] Anticholinergics such as homatropine, may help produce a dryingeffect in the nose and chest.

[0972] Antiviral agents specifically or generally modulate thebiological activity of viruses such as picornavirus, influenza virus,herpesviruses, herpes simples, herpes zoster, enteroviruses, varicellaand rhinovirus, which are associated with the common cold. Examples ofantiviral agents include neuramimidase inhibitors such as zanamivir andoseltamivir; agents for herpesviruses such as famciclovir, valaciclovir,valganciclovir, aciclovir and ganciclovir; interferons;interferon-inducers; and newer antiviral agents such as dipyridamole;ICI 130,685; impulsin; and pleconaril (VP-63843;3-[3,5-dimethyl-4[[3-(3-methyl-5-isoxazolyl)propyl]oly]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole; available under the tradename PICOVIR® from ViroPharma andSanofi-Synthelabo).

[0973] Other materials can be used along with the subject combination ofa Cox-2 selective inhibitor and at least one colds and cough activeingredient. For example, ingredients such as caffeine, potassiumcitrate, ascorbic acid and citric acid can be added to the combinations,as can such materials as fillers, dyes, binders, adsorbents,surfactants, and the like.

[0974] One embodiment of the present invention is a composition thatincludes a cycloxygenase-2 selective inhibitor and one or more colds andcough active ingredient. Any one of, or any combination of, the Cox-2selective inhibitors that are described above can be used in thecomposition. Likewise, the colds and cough active ingredient can beselected from an antihistamine, antitussive, analgesic, expectorant,decongestant, anticholinergic, antiviral agent, or a mixture of two ormore thereof.

[0975] In an embodiment, the colds and cough active ingredient comprisesan antihistamine. It is preferred that the antihistamine is selectedfrom the group consisting of azatadine, bromodiphenhydramine,brompheniramine, brompheniramine maleate, carbinoxamine,chlorpheniramine, dexchlorpheniramine, diphenhydramine, doxylamine,phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine,triprolidine, and mixtures thereof.

[0976] In another embodiment, the colds and cough active ingredientcomprises an antitussive. In preferred embodiments, the antitussive isselected from the group consisting of codeine, dihydrocodeine,hydrocodone, hydrocodone bitartrate, hydromorphone, carbetapentane,caraminphen, dextromethorphan, chlorphedianol, noscarpine, and mixturesthereof.

[0977] In another embodiment, the colds and cough active ingredientcomprises an analgesic. It preferred embodiments, the analgesic isselected from the group consisting of acetaminophen, aspirin,salicylamide, sodium salicylate, indomethacin, ibuprofen, naproxen,flubiprofen, carprofen, tiaprofenic acid, cicloprofen, detoprofen,ketorolac, etodolac, and mixtures thereof.

[0978] In another embodiment, the colds and cough active ingredientcomprises an expectorant. In preferred embodiments, the expectorantcomprises guaifenesin, glyceryl guaiacolate, terpin hydrate, ammoniumchloride, N-acetylesteine, bromhexine, ambroxol, domiodol,3-iodo-1,2-propanediol, and mixtures thereof.

[0979] In another embodiment, the colds and cough active ingredientcomprises a decongestant. In preferred embodiments, the decongestant isselected from the group consisting of ephedrine, ephinephrine,levodesoxyephedrine, oxymetazoline, naphazoline, phenylephrine,phenylpropanolamine, propylhexedrine, pseudoephedrine, xylometazoline,and mixtures thereof.

[0980] In another embodiment, the colds and cough active ingredientcomprises an anticholinergic. In preferred embodiments, theanticholinergic comprises homatropine.

[0981] In another embodiment, the colds and cough active ingredientcomprises an antiviral agent. In preferred embodiments, the antiviralagent comprises a neuramimidase inhibitor, an agent for herpesviruses,an interferon, or an interferon-inducer. In more preferred embodiments,the antiviral agent comprises dipyridamole, ICI 130,685, impulsin,pleconaril, zanamivir, oseltamivir, famciclovir, valaciclovir,valganciclovir, aciclovir (acyclovir), ganciclovir, idoxuridine,vidarabine, trifluridine, penciclovir, valacyclovir, foscarnet,ribavarin, amantadine, rimantadine, cidofovir, or two or more of thesecompounds.

[0982] Another embodiment of the present invention is a composition thatincludes a cycloxygenase-2 selective inhibitor and two or more differenttypes of colds and cough active ingredients. The Cox-2 selectiveinhibitor can be any one of, or any combination of, the Cox-2 selectiveinhibitors that are described above. The two or more different types ofcolds and cough active ingredients can be selected from any combinationof two or more of an antihistamine, antitussive, analgesic, expectorant,decongestant, anticholinergic, or an antiviral agent. Preferredembodiments of the present invention include a cyclooxygenase-2selective inhibitor in combination with any of the combinations of twoor more colds and cough active ingredients that are shown in Table 3.

[0983] Table 3: Combinations of two or more colds and cough activeingredients and trade names of commercial compositions that include thecombination. COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAMECOMBINATIONS 1 An antihistamine and an antitussive. 2 Ambenyl Cough;bromodiphenhydramine and codeine. Ambophen; Amgenal Cough; Bromanyl;Bromotuss with Codeine; 3 chlorpheniramine and codeine. 4 EffectiveStrength chlorpheniramine and dextromethorphan. Cough Formula; PrimatussCough Mixture; Scot-Tussin DM; Tricodene Sugar Free; 5 S-T-Forte 2;chlorpheniramine and hydrocodone. Tussionex Pennkinetic; 6phenyltoloxamine and hydrocodone. 7 Pentazine VC w/ promethazine andcodeine. Codeine; Phenergan with Codeine; Pherazine w/Codeine; 8Phenameth DM; promethazine and dextromethorphan. Phenergan withDextromethorphan; Pherazine DM; Promethazine DM; Prometh w/Dextromethorphan; 9 Tricodene; pyrilamine and codeine. 10 Anantihistamine, an antitussive, and an analgesic. 11 doxylamine, codeineand acetaminophen. 12 An antihistamine, an antitussive, and anexpectorant. 13 bromodiphenhydramine, diphenhydramine, codeine, ammoniumchloride and potassium guaiacolsulfonate. 14 diphenhydramine, codeineand ammonium chloride. 15 diphenhydramine, dextromethorphan and ammoniumchloride. 16 pheniramine, codeine and guaifenesin. 17 Citra-Forte;pheniramine, pyrilamine, hydrocodone, potassium citrate and ascorbicacid. 18 Citra-Forte; chlorpheniramine, pheniramine, pyrilamine,phenylephrine, hydrocodone salicylamide, caffeine and ascorbic acid. 19promethazine, codeine and potassium guaiacolsulfonate. 20 Anantihistamine, a decongestant and an antitussive. 21 brompheniramine,phenylephrine, phenylpropanolamine and codeine. 22 brompheniramine,phenylephrine, phenylpropanolamine and dextromethorphan. 23 Bromonate DCCough; brompheniramine, phenylpropanolamine and Bromphen DC withcodeine. Codeine Cough; Dimetane-DC Cough; Myphetane DC Cough;Poly-Histine-CS; 24 Dimetapp DM; brompheniramine, phenylpropanolamineand Dimetapp DM Cold & dextromethorphan. Cough; Dimetapp MaximumStrength Cold & Cough Liqui-Gels; Histinex DM; lohist DM; Liqui-HistineDM; Poly-Histine-DM; Siltapp w/ Dextromethorphan Cough & Cold; 25Bromarest DX Cough; brompheniramine, pseudoephedrine and Bromatene DXCough; dextromethorphan. Bromfed DM; Bromphen DX Cough; Brotane DXCough; Dimetane-DX Cough; Myphetane DX Cough; 26 Carbinoxaminecarbinoxamine, pseudoephidrine and Compound; dextromethorphan.Carbinoxamine Compound Drops; Carbodec DM; Carbodec DM Drops; Cardec DM;Cardec DM Drops; Cardec DM Pediatric; Pseudo-Car DM; Rondamine-DM Drops;Rondec-DM; Rondec-DM Drops; Sildec-DM; Sildec-DM Oral Drops; Tussafed;Tussafed Drops; 27 Rentamine Pediatric; chlorpheniramine, ephedrine,phenylephrine Rynatuss; and carbetapentane. Rynatuss Pediatric;Tri-Tannate Plus Pediatric; 28 Atuss DM; chlorpheniramine, phenylephrineand Cerose DM; dextromethorphan. Dondril; 29 Anaplex HD;chlorpheniramine, phenylephrine and Atuss HD; hydrocodone. Chlorgest-HD;ED-TLC; ED Tuss HC; Edagen-HD; Endal-HD; Endal-HD Plus; Histinex HC;Histussin HC; lodal HD; lotussin HC; Med-Hist HC; Nasatuss; Para-HistHD; Unituss HC; Vanex-HD; 30 T-Koff; chlorpheniramine, phenylephrine,phenylpropanolamine and codeine. 31 Cophene-S; chlorpheniramine,phenylephrine, Vanex Grape; phenylpropanolamine and dihydrocodeine. 32chlorpheniramine, phenylpropanolamine and caramiphen. 33 Cheracol Plus;chlorpheniramine, phenylpropanolamine and Kophane Cough anddextromethorphan. Cold Formula; Myminicol; Snaplets-Multi; Threamine DM;Triaminicol Multi- Symptom Cold and Cough Medicine; TriaminicTriaminicol; Tricodene Forte; Tricodene NN; Triminol Cough; 34 CodehistDH; chlorpheniramine, pseudoephedrine and Decohistine DH; codeine.Dihistine DH; Medahist DH; Novahistine DH Liquid; Phenhist DH w/Codeine; Ryna-C Liquid; 35 PediaCare Cough- chlorpheniramine,pseudoephedrine and Cold; dextromethorphan. PediaCare Night RestCough-Cold Liquid; Rescon-DM; Rhinosyn-DM; Triaminic Night Time; TussarDM; Vicks Children's NyQuil Cold/Cough Relief; Vicks Pediatric 44 MMulti-Symptom Cough & Cold; 36 Histinex PV; chlorpheniramine,pseudoephedrine and Promist HD Liquid; hydrocodone. P-V-Tussin; 37diphenylpyraline, phenylephrine and dextromethorphan. 38 doxylamine,etafedrine and hydrocodone. 39 pheniramine, phenylephrine anddextromethorphan. 40 Rolatuss w/ pheniramine, pyrilamine, phenylephrine,Hydrocodone; phenylpropanolamine and hydrocodone. Ru-Tuss withHydrocodone Liquid; Statuss Green; 41 pyrilamine, phenylpropanolamineand codeine. 42 pheniramine, pyrilamine, phenylpropanolamine anddextromethorphan. 43 pheniramine, pyrilamine, phenylpropanolamine andhydrocodone. 44 Phenameth VC with promethazine, phenylephrine andcodeine. Codeine; Phenergan VC with Codeine; Pherazine VC with Codeine;Promethazine VC w/ Codeine; Promethist w/ Codeine; Prometh VC withCodeine; 45 promethazine, pseudoephedrine and dextromethorphan. 46Codimal PH; pyrilamine, phenylephrine and codeine. 47 Codimal DM;pyrilamine, phenylephrine and dextromethorphan. 48 Codimal DH;pyrilamine, phenylephrine and hydrocodone. 49 Actagen-C-Cough;triprolidine, pseudoephedrine and codeine. Actifed with Codeine Cough;Allerfrin with Codeine; Aprodine with Codeine; Triacin C Cough; Triafedw/ Codeine; Trifed-C Cough; 50 triprolidine, pseudoephedrine anddextromethorphan. 51 An antihistamine, a decongestant, an antitussiveand an analgesic. 52 Omnicol; chlorpheniramine, phenindamine,phenylephrine, dextromethorphan, acetaminophen, salicylamide, caffeineand ascorbic acid. 53 chlorpheniramine, pheniramine, pyrilamine,phenylephrine, hydrocodone, salicylamide, caffeine and ascorbic acid. 54Improved Sino-Tuss; chlorpheniramine, phenylephrine, dextromethorphan,acetaminophen and salicylamide. 55 Hycomine Compound; chlorpheniramine,phenylephrine, hydrocodone, acetaminophen and caffeine. 56 Alka-SeltzerPlus Flu chlorpheniramine, phenylpropanolamine, & Body Aches;dextromethorphan and acetaminophen. Comtrex Maximum Strength Multi-Symptom Liqui-Gels; Comtrex Multi- Symptom Cold Reliever; Contac SevereCold & Flu Caplets; 57 Alka-Seltzer Plus Cold chlorpheniramine,phenylpropanolamine, and Cough; dextromethorphan and aspirin. 58chlorpheniramine, pseudoephedrine, codeine and acetaminophen. 59Alka-Seltzer Plus Cold chlorpheniramine, pseudoephedrine, and CoughMedicine dextromethorphan and acetaminophen. Liqui-Gels; Children'sTylenol Cold Plus Cough Multi Symptom; Comtrex Nighttime; ComtrexNighttime Maximum Strength Cold, Cough and Flu Relief; Comtrex NighttimeMaximum Strength Cold and Flu Relief; Kolephrin/DM Cough and ColdMedication; Mapap Cold Formula; TheraFlu Flu, Cold & Cough Medicine;TheraFlu Nighttime Maximum Strength Flu, Cold & Cough; Tylenol ColdMedication; Tylenol Cold Medication Caplets; Tylenol Cold Multi-Symptom; Vicks 44 M Cough, Cold and Flu Relief; Vicks 44 M Cough, Coldand Flu Relief LiquidCaps; 60 Alka-Seltzer Plus doxylamine,phenylpropanolamine, Night-Time Cold; dextromethorphan and aspirin.Co-Apap; 61 Alka-Seltzer Plus doxylamine, pseudoephedrine, Night-TimeCold Liqui- dextromethorphan and acetaminophen. Gels; All-Night ColdFormula; Genite; Nytcold Medicine; Robitussin Night-Time Cold Formula;Vicks NyQuil Hot Therapy; Vicks NyQuil Multi- Symptom Cold/FluLiquiCaps; Vicks NyQuil Multi- Symptom Cold/Flu Relief; 62 RobitussinNight pyrilamine, pseudoephedrine, Relief; dextromethorphan andacetaminophen. 63 An antihistamine, a decongestant, an antitussive andan expectorant. 64 brompheniramine, phenylephrine, phenylpropanolamine,codeine and guaifenesin. 65 comprises brompheniramine, phenylephrine,phenylpropanolamine, hydrocodine and guaifenesin. 66 Quelidrine Cough;chlorpheniramine, ephedrine, phenylephrine, dextromethorphan, ammoniumchloride and ipecac. 67 Tusquelin; chlorpheniramine, phenylephrine,phenylpropanolamine, dextromethorphan, potassium guaiacolsulfonate andipecac. 68 Rolatuss Expectorant; chlorpheniramine, phenylephrine,codeine and ammonium chloride. 69 Pediacof Cough; chlorpheniramine,phenylephrine, codeine and Pedituss Cough; potassium iodide. 70Donatussin; chlorpheniramine, phenylephrine, dextromethorphan andguaifenesin. 71 Father John' Medicine chlorpheniramine, phenylephrine,Plus; dextromethorphan, guaifenesin and ammonium chloride. 72Cophene-XP; chlorpheniramine, phenylephrine, phenylpropanolamine,carbetapentane and potassium guaiacolsulfonate. 73 chlorpheniramine,phenyltoloxamine, ephedrine, codeine and guaiacol carbonate. 74chlorpheniramine, pseudoephedrine, dextromethorphan and guaifenesin. 75Prominicol Cough; pheniramine, pyrilamine, phenylpropanolamine,dextromethorphan and ammonium chloride. 76 Triaminic Expectorantpheniramine, pyrilamine, phenylpropanolamine, DH hydrocodone andguaifenesin. 77 S-T-Forte; pheniramine, phenylephrine,phenylpropanolamine, hydrocodone and guaifenesin. 78 promethazine,phenylephrine, codeine and potassium guaiacolsulfonate. 79 pyrilamine,phenylephrine, hydrocodone and ammonium chloride. 80 Phanatussin;pyrilamine, phenylpropanolamine, dextromethorphan and guaifenesin. 81triprolidine, pseudoephedrine, codeine and guaifenesin. 82 Anantihistamine, a decongestant, an antitussive, an expectorant and ananalgesic. 83 Tussirex; pheniramine, phenylephrine, codeine, sodiumcitrate, sodium salicylate and caffeine. 84 An antihistamine, adecongestant and an expectorant. 85 brompheniramine, phenylephrine,phenylpropanolamine and guaifenesin. 86 Bronkotuss chlorpheniramine,ephedrine and guaifenesin. Expectorant; 87 Donatussin Drops;chlorpheniramine, phenylephrine and guaifenesin. 88 chlorpheniramine,phenylpropanolamine and guaifenesin. 89 Lanatuss Expectorant;chlorpheniramine, phenylpropanolamine, guaifenesin, sodium citrate andcitric acid. 90 chlorpheniramine, pseudoephedrine and guaifenesin. 91Polaramine dexchlorpheniramine, pseudoephedrine and Expectorant;guaifenesin. 92 promethazine, phenylephrine and potassiumguaiacolsulfonate. 93 An antihistamine, a decongestant, an expectorantand an analgesic. 94 Gelpirin-CCF; chlorpheniramine,phenylpropanolamine, guaifenesin and acetaminophen. 95 An antihistamineand an expectorant. 96 Drixoral Cough & Sore promethazine and potassiumThroat Liquid Caps; guaiacolsulfonate. Tylenol Multi-Symptom Cough; 97An antitussive and an analgesic. 98 dextromethorphan and acetaminophen.99 An antitussive and an antichlolinergic. 100 Codan; hydrocodone andhomatropine. Hycodan; Hydromet; Hydropane; Tussigon; 101 An antitussiveand an expectorant. 102 Cheracol; codeine, ammonium chloride andguaifenesin. 103 Calcidrine; codeine and calcium iodide. 104 Brontex;codeine and guaifenesin. Glydeine Cough; Guaituss A.C.; Mytussin AC;Robafen AC Cough; Robitussin A-C; Tolu-Sed Cough; Tussi-Organidin NRLiquid; Tussi-Organidin-S NR Liquid; 105 lophen-C Liquid; codeine andiodated glycerol. 106 Anti-Tuss DM dextromethorphan and guaifenesin.Expectorant; Benylin Expectorant; Cheracol D Cough; Children's FormulaCough; Diabetic Tussin DM; Extra Action Cough; Fenesin DM; Genatuss DM;Glycotuss-dM; Guaimid D.M. Liquid; Guaitussin w/ Dextromethorphan;Halotussin-DM; Humibid DM; Humibid DM Pediatric; lobid DM; KolephrinGG/DM; Muco-Fen DM; Mytussin DM; Naldecon Senior DX; Phanatuss;Respa-DM; Rhinosyn-DMX Expectorant; Robafen DM; Robitussin-DM; SafeTussin 30; Scot-Tussin Senior Clear; Silexin Cough; Siltussin-DM;Supressin DM; Supressin DM Caplets; Syracol CF; Tolu-Sed DM Touro DM;Tuss-DM; Tussi-Organidin DM NR Liquid; Tussi-Organidin DM-S NR Liquid;Uni-tussin DM; Unproco; Vicks 44E Cough & Chest Congestion; VicksPediatric 44E; 107 lophen DM; dextromethorphan and iodated glycerol.Tusso-DM; 108 Atuss EX; hydrocodone and guaifenesin. Codiclear DH;Co-Tuss V; Hycotuss Expectorant; Kwelcof Liquid; Pneumotussin HC;Vicodin Tuss; 109 Entuss Expectorant; hydrocodone and potassiumguaiacolsulfonate. Marcof Expectorant; 110 Dilaudid Cough; hydromorphoneand guaifenesin. 111 A decongestant and an antitussive. 112phenylephrine and codeine. 113 Nalex DH; phenylephrine and hydrocodone.114 Ordrine AT; phenylpropanolamine and caramiphen. Rescaps-D S.R.;Tuss-Ade; Tuss-Allergine Modified T.D.; Tussogest; 115 Snaplets-DM;phenylpropanolamine and dextromethorphan. Triaminic-DM Cough Relief;Tricodene Pediatric; 116 Codamine; phenylpropanolamine and hydrocodone.Codamine Pediatric Hycomine; Hycomine Pediatric; Hydromine; HydrominePediatric; Hydrophen; 117 Nucofed; pseudoephedrine and codeine. 118Drixoral Cough & pseudoephedrine and dextromethorphan. Congestion LiquidCaps; Effective Strength Cough Formula with Decongestant; RobitussinMaximum Strength Cold and Cough; Robitussin Pediatric Cold & Cough;Triaminic AM Non- Drowsy Cough and Decongestant; Tuss-DA; Vicks 44 Coughand Cold Relief Non- Drowsy LiquiCaps; Vicks 44D Cough and HeadCongestion; Vicks Pediatric 44D Cough & Head Decongestion; 119 De-Tuss;pseudoephedrine and hydrocodone. Detussin Liquid; Tyrodone; 120 Adecongestant, an antitussive and an analgesic. 121 Saleto-CF;phenylpropanolamine, dextromethorphan and acetaminophen. 122Alka-Seltzer Plus Flu pseudoephedrine, dextromethorphan and & Body Achesacetaminophen. Medicine Liqui-Gels; Co-Complex DM Caplets; ComtrexDaytime Caplets; Contrex Daytime Maximum Strength Cold, Cough, and FluRelief; Comtrex Daytime Maximum Strength Cold and Flu Relief; ComtrexMulti- Symptom Maximum Strength Non-Drowsy Caplets; Contac Cold/Flu DayCaplets; Contac Severe Cold & Flu Non-Drowsy Caplets; Ornex Severe ColdNo Drowsiness Caplets; Sudafed Severe Cold Formula; Sudafed Severe ColdFormula Caplets; TheraFlu Maximum Strength Non-Drowsy Formula Flu, Cold& Cough Medicine; TheraFlu Maximum Strength Non-Drowsy Formula Flu, Cold& Cough Medicine Caplets; Triaminic Sore Throat Formula; Tylenol Coldand Flu Non Crowsiness Powder; Tylenol Cold Medication, Non- DrowsyCaplets; Tylenol Cold Medication, Non- Drowsy Caplets; Tylenol MaximumStrength Flu Gelcaps; Tylenol Multi-Symptom Cough with Decongestant; 123A decongestant, an antitussive and an expectorant. 124 ephedrine,carbetapentane and guaifenesin. 125 Dexafed Cough; phenylephrine,dextromethorphan and Supressin DM Plus; guaifenesin. Tussex Cough; 126Cophene-X; phenylephrine, phenylpropanolamine, carbetapentane andpotassium guaiacolsulfonate. 127 Donatussin DC; phenylephrine,hydrocodone and guaifenesin. 128 Codegest Expectorant;phenylpropanolamine, codeine and Conex with Codeine guaifenesin. Liquid;C-Tussin Expectorant; Endal Expectorant; Naldecon-CX Adult Liquid;Statuss Expectorant; Triaminic Expectorant with Codeine; 129 Anatuss;phenylpropanolamine, dextromethorphan and GuaiCough CF; guaifenesin.Guaituss CF; Ipsatol Cough Formula for Children and Adults; Kiddy Koff;Naldecon-DX Adult Liquid; Naldecon-DX Children's Syrup; Naldecon-DXPediatric Drops; Robafen CF; Robitussin-CF; Siltussin-CF; 130 Anatuss;phenylpropanolamine, dextromethorphan, guaifenesin and acetaminophen.131 Deproist Exectorant pseudoephedrine, codeine and guaifenesin. withCodeine; Dihistine Expectorant; Guaituss DAC; Mytussin DAC; NovagestExpectorant w/Codeine; Novahistine Expectorant; Nucochem Expectorant;Nucochem Pediatric Expectorant; Nucofed Expectorant; Nucofed PediatricExpectorant; Nucotuss Expectorant; Nucotuss Pediatric Expectorant;Phenhist Expectorant; Robafen DAC; Robitussin-DAC; Ryna-CX Liquid;Tussar-2; Tussar SF; 132 Ambenyl-D pseudoephedrine, dextromethorphan andDecongestant Cough guaifenesin. Formula; Anatuss DM; Benylin Multi-Symptom; Concentrin; Dimacol Caplets; Dorcol Children's Cough;Novahistine DMX Liquid; PediaPressin Pediatric Drops; Primatuss CoughMixture 4D; Rhinosyn-X; Robitussin Cold and Cough Liqui-Gels; Ru-TussExpectorant; Sudafed Children's Non-Drowsy Cold & Cough; SudafedChildren's Cold & Cough; 133 Cophene-XP; pseudoephedrine, hydrocodoneand Detussin Expectorant; guaifenesin. Duratuss HD; Entuss-D Jr;Med-Hist Exp; SRC Expectorant; Tussafin Expectorant; Vanex Expectorant;134 Entuss-D; pseudoephedrine, hydrocodone and potassium Protuss-D;guaiacolsulfonate. 135 A decongestant, an antitussive, an expectorantand an analgesic. 136 phenylpropanolamine, dextromethorphan, guaifenesinand acetaminophen. 137 Comtrex Cough pseudoephedrine, dextromethorphan,Formula; guaifenesin and acetaminophen. Robitussin Cold, Cough & FluLiqui- Gels; Sudafed Cold & Cough Liquid Caps; Vicks DayQuil Multi-Symptom Cold/Flu LiquiDaps; Vicks DayQuil Multi- Symptom Cold/FluRelief; 138 A decongestant and an expectorant. 139 Broncholate;ephedrine and guaifenesin. 140 KIE; ephedrine and potassium iodide. 141Deconsal Pediatric; phenylephrine and guaifenesin. Endal; Rescon-GG;Sinupan; 142 Ami-Tex; phenylephrine, phenylpropanolamine and BanexLiquid; guaifenesin. Contuss; Despec; Despec SF; Dura-Gest; Dura-Tex;Enomine; Entex; Entex Liquid; Norel; Sil-Tex; 143 Ami-Tex LA;phenylpropanolamine and guaifenesin. Banex-LA; Conex; Despec-SR Caplets;Dura-Vent; Entex LA; Exgest LA; Guaifenex PPA 75; Guaipax; MyminicExpectorant; Naldecon-EX Children's Syrup; Naldecon-EX Pediatric Drops;Partuss LA; Phenylfenesin LA; Profen II; Profen-LA; ProminicExpectorant; Rymed-TR Caplets; Silaminic Expectorant; Sildecon-EPediatric Drops; SINUvent; Snaplets-EX; Stamoist LA; TriaminicExpectorant; Triphenyl Expectorant; ULR-LA; Vicks DayQuil Simus Pressureand Congestion Relief Caplets; 144 Anatuss LA; pseudoephedrine andguaifenesin. Congess JR; Congess SR; Congestac Caplets; Deconsal II;Duratuss; Entex PSE; Eudal-SR; Expressin 400 Caplets; Glycofed; GP-500;Guaifed; Guaifed-PD; Guaifenex PSE 60; Guaifenex PSE 120; GuaiMAX-D;Guaitab; Guaivent; Guaivent PD; Guai-Vent/PSE; GuaiCough PE; GuaitussPE; Humibid Guaifenesin Plus; losal II; Nalex; Nalex Jr; Nasabid;Nasatab LA; PanMist-JR; Respa-1^(st); Respaire-60 SR; Respaire-120 SR;Robitussin-PE; Robitussin Severe Congestion Liqui-Gels; Ru-Tuss DE;Rymed; Rymed Liquid; Sinufed Timecelles; Sinutab Non-Drying NoDrowsiness Liquid Caps; Stamoist E; Sudafed Non-Drowsy Non-Drying SinusLiquid Caps; Sudal 60/500; Sudal 120/600; Touro LA Caplets; Tuss-LA;V-Dec-M; Versacaps; Zephrex; Zephrex-LA; 145 A decongestant, anexpectorant and an analgesic. 146 Fendol; phenylephrine, guaifenesin,acetaminophen, salicylamide and caffeine. 147 An antihistamine and adecongestant 148 Alerid-D cetirzine and pseudoephedrine 149 ClaritinReditabs loratadine and pseudoephedrine Claritin 24-Hour Claritin12-Hour

[0984] In an embodiment of the present method, a subject in need ofprevention, treatment or amelioration of a cold and/or a cough istreated by administering to the subject a cyclooxygenase-2 selectiveinhibitor or prodrug thereof and one or more colds and cough activeingredient. In one embodiment, the subject is treated with an amount ofa colds and cough active ingredient and an amount of a Cox-2 selectiveinhibitor, where the amount of the colds and cough active ingredient andthe amount of the Cox-2 selective inhibitor together provide a dosage oramount of the combination that is sufficient to constitute an effectiveamount of the combination. The effective amount can be a therapeuticamount, and it can be an amount that is an effective amount for theprevention, treatment or amelioration of a cold or a cough.

[0985] As used herein, an “effective amount” means the dose or effectiveamount to be administered to a patient and the frequency ofadministration to the subject which is readily determined by one orordinary skill in the art, by the use of known techniques and byobserving results obtained under analogous circumstances. The dose oreffective amount to be administered to a patient and the frequency ofadministration to the subject can be readily determined by one ofordinary skill in the art by the use of known techniques and byobserving results obtained under analogous circumstances. In determiningthe effective amount or dose, a number of factors are considered by theattending diagnostician, including but not limited to, the potency andduration of action of the compounds used; the nature and severity of theillness to be treated as well as on the sex, age, weight, general healthand individual responsiveness of the patient to be treated, and otherrelevant circumstances.

[0986] The phrase “therapeutically-effective” indicates the capabilityof an agent to prevent, or improve the severity of, the disorder, whileavoiding adverse side effects typically associated with alternativetherapies. The phrase “therapeutically-effective” is to be understood tobe equivalent to the phrase “effective for the treatment, prevention, orinhibition”, and both are intended to qualify the amount of each agentfor use in the combination therapy which will achieve the goal ofimprovement in the severity of neurological or psychiatric disorder andthe frequency of incidence over treatment of each agent by itself, whileavoiding adverse side effects typically associated with alternativetherapies.

[0987] Those skilled in the art will appreciate that dosages may also bedetermined with guidance from Goodman & Goldman's The PharmacologicalBasis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711.Furthermore, detailed prescribing information is available over theinternet, or from the manufacturer or distributor, for each of thecommercial colds and cough active ingredients that are described inTable 3.

[0988] In the present method, the amount of the colds and cough activeingredient that is used is such that, when administered with thecyclooxygenase-2 selective inhibitor, it is sufficient to constitute aneffective amount of the combination. It is preferred that the dosageamount of the colds and cough active ingredient and the dosage amount ofthe cyclooxygenase-2 selective inhibitor constitute a therapeuticallyeffective amount of the combination.

[0989] It is well known that different colds and cough activeingredients have different levels of potency and that recommended dosagelevels vary considerably. The recommended dosage level for a commercialcolds and cough active ingredient can be found in the prescribinginformation that is published by the distributor as described above.

[0990] The frequency of dose will depend upon the half-life of the coldsand cough active ingredient molecule. If the colds and cough activeingredient has a short half life (e.g. from about 2 to 10 hours) it maybe necessary to give one or more doses per day. Alternatively, if thecolds and cough active ingredient has a long half-life (e.g. from about2 to about 15 days) it may only be necessary to give a dosage once perday, per week, or even once every 1 or 2 months. A preferred dosage rateis to administer the dosage amounts described above to a subject onceper day.

[0991] For the purposes of calculating and expressing a dosage rate, alldosages that are expressed herein are calculated on an averageamount-per-day basis irrespective of the dosage rate. For example, one100 mg dosage of an ingredient taken once every two days would beexpressed as a dosage rate of 50 mg/day. Similarly, the dosage rate ofan ingredient where 50 mg is taken twice per day would be expressed as adosage rate of 100 mg/day.

[0992] For the purposes of calculation of a dosage rate for the presentmethod, the weight of an adult human is assumed to be 70 kg.

[0993] The amount of Cox-2 selective inhibitor that is used in thesubject method may be an amount that, when administered with the coldsand cough active ingredient, is sufficient to constitute an effectiveamount of the combination. Preferably, such amount would be sufficientto provide a therapeutically effective amount of the combination. Thetherapeutically effective amount can also be described herein as anamount that is effective for the prevention, treatment or ameliorationof a cold and/or a cough.

[0994] In the present method, the amount of Cox-2 selective inhibitorthat is used in the novel method of treatment preferably ranges fromabout 0.01 to about 100 milligrams per day per kilogram of body weightof the subject (mg/day·kg), more preferably from about 0.1 to about 50mg/day·kg, even more preferably from about 1 to about 20 mg/day·kg.

[0995] When the Cox-2 selective inhibitor comprises rofecoxib, it ispreferred that the amount used is within a range of from about 0.15 toabout 1.0 mg/day·kg, and even more preferably from about 0.18 to about0.4 mg/day·kg.

[0996] When the Cox-2 selective inhibitor comprises etoricoxib, it ispreferred that the amount used is within a range of from about 0.5 toabout 5 mg/day·kg, and even more preferably from about 0.8 to about 4mg/day·kg.

[0997] When the Cox-2 selective inhibitor comprises celecoxib, it ispreferred that the amount used is within a range of from about 1 toabout 10 mg/day·kg, even more preferably from about 1.4 to about 8.6mg/day·kg, and yet more preferably from about 2 to about 3 mg/day·kg.

[0998] When the Cox-2 selective inhibitor comprises parecoxib sodium, itis preferred that the amount used is within a range of from about 0.1 toabout 3 mg/day·kg, and even more preferably from about 0.3 to about 1mg/day·kg.

[0999] The combination of a colds and cough active ingredient and aCox-2 selective inhibitor can be supplied in the form of a noveltherapeutic composition that is believed to be within the scope of thepresent invention. The relative amounts of each component in thetherapeutic composition may be varied and may be as described justabove. The colds and cough active ingredient and Cox-2 selectiveinhibitor that are described above can be provided in the therapeuticcomposition so that the preferred amounts of each of the components aresupplied by a single dosage, a single injection or a single capsule forexample, or, by up to four, or more, single dosage forms.

[1000] When the novel combination is supplied along with apharmaceutically acceptable carrier, a pharmaceutical composition isformed. A pharmaceutical composition of the present invention isdirected to a composition suitable for the prevention, treatment oramelioration of colds and/or coughs. The pharmaceutical compositioncomprises a pharmaceutically acceptable carrier, one or more colds andcough active ingredient, and a cyclooxygenase-2 selective inhibitor.

[1001] Pharmaceutically acceptable carriers include, but are not limitedto, physiological saline, Ringer's, phosphate solution or buffer,buffered saline, and other carriers known in the art. Pharmaceuticalcompositions may also include stabilizers, anti-oxidants, colorants, anddiluents. Pharmaceutically acceptable carriers and additives are chosensuch that side effects from the pharmaceutical compound are minimizedand the performance of the compound is not canceled or inhibited to suchan extent that treatment is ineffective.

[1002] The term “pharmacologically effective amount” shall mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, system, animal or human that is beingsought by a researcher or clinician. This amount can be atherapeutically effective amount.

[1003] The term “pharmaceutically acceptable” is used herein to meanthat the modified noun is appropriate for use in a pharmaceuticalproduct. Pharmaceutically acceptable cations include metallic ions andorganic ions. More preferred metallic ions, include, but are not limitedto, appropriate alkali metal salts, alkaline earth metal salts and otherphysiological acceptable metal ions. Exemplary ions include aluminum,calcium, lithium, magnesium, potassium, sodium and zinc in their usualvalences. Preferred organic ions include protonated tertiary amines andquaternary ammonium cations, including in part, trimethylamine,diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. Exemplary pharmaceutically acceptable acids include, withoutlimitation, hydrochloric acid, hydroiodic acid, hydrobromic acid,phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid,formic acid, tartaric acid, maleic acid, malic acid, citric acid,isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronicacid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid,aspartic acid, glutamic acid, benzoic acid, and the like.

[1004] Notwithstanding the above description of certain alkali metal andalkali earth metal ions as being pharmaceutically acceptable cations, itshould be recognized that it is preferred that the cold and cough activeingredient of the present invention be one that is free of an isolatedmetal salt of the cold and cough active ingredient. In other words, whenthe colds and cough active ingredient is one that can exist in a freeacid form or in a metal salt form, it is preferred that at least someportion of the cold and cough active ingredient be present in its freeacid form, rather than in an isolated metal salt form. It is morepreferred that when the cold and cough active ingredient comprises ananalgesic, the analgesic is free of an isolated metal salt of theanalgesic. In other words, it is preferred that at least some portion ofthe analgesic be present in its free acid form, rather than its metalsalt form. It is yet more preferred that when the cold and cough activeingredient comprises acetaminophen, the acetaminophen is free of anisolated metal salt of the acetaminophen. In other words, it ispreferred that at least some portion of the acetaminophen be present inits free acid form, rather than its metal salt form.

[1005] In some cases, in particular where a subject is adverselyaffected by acetaminophen, it is preferred that the novel method andcompositions be free of acetaminophen.

[1006] Also included in the combination of the invention are theisomeric forms and tautomers and the pharmaceutically-acceptable saltsof antipsychotic agents and cyclooxygenase-2 selective inhibitors.Illustrative pharmaceutically acceptable salts are prepared from formic,acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric,enanthic, decanoic and galacturonic acids.

[1007] Suitable pharmaceutically-acceptable base addition salts ofcompounds of the present invention include metallic ion salts andorganic ion salts. More preferred metallic ion salts include, but arenot limited to, appropriate alkali metal (group Ia) salts, alkalineearth metal (group IIa) salts and other physiological acceptable metalions. Such salts can be made from the ions of aluminum, calcium,lithium, magnesium, potassium, sodium and zinc. Preferred organic saltscan be made from tertiary amines and quaternary ammonium salts,including in part, trimethylamine, diethylamine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All of theabove salts can be prepared by those skilled in the art by conventionalmeans from the corresponding compound of the present invention.

[1008] The method and compositions of the present invention are usefulfor, but not limited to, the prevention, inhibition, and amelioration ofa cold and/or a cough in a subject that is need of such treatment. Byway of example, the method and compositions would be useful for theprevention, treatment and amelioration of runny nose, nasal congestion,lung congestion, bronchial irritation, neuritis, neuralgia, sore throat,pain, aches, inflammation, sneezing, coughing, upper respiratoryinfections, allergic rhinitis, otitis, sinusitis, coryza, itchy andwatery eyes, and the like, or any two or more of the symptoms describedabove.

[1009] The terms “treating” or “to treat” mean to alleviate symptoms,eliminate the causation either on a temporary or permanent basis, or toprevent or slow the appearance of symptoms. The term “treatment”includes alleviation, elimination of causation of or prevention of coldsand/or cough, or the symptoms associated with, but not limited to thosedisorders. Besides being useful for human treatment, these combinationsare also useful for treatment of mammals, including horses, dogs, cats,rats, mice, sheep, pigs, etc.

[1010] The term “subject” for purposes of treatment includes a subjectwho is in need of the prevention of, or who has a cold or a cough. Thesubject is typically an animal, and yet more typically is a mammal.“Mammal”, as that term is used herein, refers to any animal classifiedas a mammal, including humans, domestic and farm animals, and zoo,sports, or pet animals, such as dogs, horses, cats, cattle, etc.,Preferably, the mammal is a human.

[1011] For methods of prevention, the subject is any animal subject, andpreferably is a subject that is in need of prevention and/or treatmentof a cold and/or a cough. The subject may be a human subject who is atrisk for a cold or cough. The subject may be at risk due to geneticpredisposition, sedentary lifestyle, diet, exposure to disorder-causingagents, exposure to pathogenic agents and the like.

[1012] The subject pharmaceutical compositions may be administeredenterally and parenterally. Parenteral administration includessubcutaneous, intramuscular, intradermal, intramammary, intravenous, andother administrative methods known in the art. Enteral administrationincludes solution, tablets, sustained release capsules, enteric coatedcapsules, and syrups. When administered, the pharmaceutical compositionmay be at or near body temperature.

[1013] The phrases “combination therapy”, “co-administration”,“administration with”, or “co-therapy”, in defining the use of acyclooxygenase-2 inhibitor agent and a colds and cough activeingredient, is intended to embrace administration of each agent in asequential manner in a regimen that will provide beneficial effects ofthe drug combination, and is intended as well to embraceco-administration of these agents in a substantially simultaneousmanner, such as in a single capsule or dosage device having a fixedratio of these active agents or in multiple, separate capsules or dosagedevices for each agent, where the separate capsules or dosage devicescan be taken together contemporaneously, or taken within a period oftime sufficient to receive a beneficial effect from both of theconstituent agents of the combination.

[1014] Although the combination of the present invention may includeadministration of a colds and cough active ingredient component and acyclooxygenase-2 selective inhibitor component within an effective timeof each respective component, it is preferable to administer bothrespective components contemporaneously, and more preferable toadminister both respective components in a single delivery dose.

[1015] In particular, the combinations of the present invention can beadministered orally, for example, as tablets, coated tablets, dragees,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be, for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, maizestarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

[1016] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredients are mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredients are present assuch, or mixed with water or an oil medium, for example, peanut oil,liquid paraffin, or olive oil.

[1017] Aqueous suspensions can be produced that contain the activematerials in admixture with excipients suitable for the manufacture ofaqueous suspensions. Such excipients are suspending agents, for example,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gumtragacanth and gum acacia; dispersing or wetting agents may benaturally-occurring phosphatides, for example lecithin, or condensationproducts of an alkylene oxide with fatty acids, for examplepolyoxyethylene stearate, or condensation products of ethylene oxidewith long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyoxyethylene sorbitan monooleate.

[1018] The aqueous suspensions may also contain one or morepreservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one ormore coloring agents, one or more flavoring agents, or one or moresweetening agents, such as sucrose or saccharin.

[1019] Oily suspensions may be formulated by suspending the activeingredients in an omega-3 fatty acid, a vegetable oil, for examplearachis oil, olive oil, sesame oil or coconut oil, or in a mineral oilsuch as liquid paraffin. The oily suspensions may contain a thickeningagent, for example beeswax, hard paraffin or cetyl alcohol.

[1020] Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

[1021] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, a suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[1022] Syrups and elixirs containing the novel combination may beformulated with sweetening agents, for example glycerol, sorbitol orsucrose. Such formulations may also contain a demulcent, a preservativeand flavoring and coloring agents.

[1023] The subject combinations can also be administered parenterally,either subcutaneously, or intravenously, or intramuscularly, orintrasternally, or by infusion techniques, in the form of sterileinjectable aqueous or olagenous suspensions. Such suspensions may beformulated according to the known art using those suitable dispersing ofwetting agents and suspending agents which have been mentioned above, orother acceptable agents. The sterile injectable preparation may also bea sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,n-3 polyunsaturated fatty acids may find use in the preparation ofinjectables.

[1024] The subject combination can also be administered by inhalation,in the form of aerosols or solutions for nebulizers, or rectally, in theform of suppositories prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperature butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and poly-ethyleneglycols.

[1025] The novel compositions can also be administered topically, in theform of creams, ointments, jellies, collyriums, solutions orsuspensions.

[1026] Daily dosages can vary within wide limits and will be adjusted tothe individual requirements in each particular case. In general, foradministration to adults, an appropriate daily dosage has been describedabove, although the limits that were identified as being preferred maybe exceeded if expedient. The daily dosage can be administered as asingle dosage or in divided dosages.

[1027] Various delivery systems include capsules, tablets, and gelatincapsules, for example.

[1028] The present invention further comprises kits that are suitablefor use in performing the methods of prevention, treatment, orinhibition described above. In one embodiment, the kit contains a firstdosage form comprising one or more colds and cough active ingredient inone or more of the forms identified above and a second dosage formcomprising one or more of the cyclooxygenase-2 selective inhibitors orprodrugs thereof identified above, in quantities sufficient to carry outthe methods of the present invention. Preferably, the first dosage formand the second dosage form together comprise a therapeutically effectiveamount of the compounds for the treatment, prevention, or ameliorationof a cold and/or a cough.

[1029] The following examples describe embodiments of the invention.Other embodiments within the scope of the claims herein will be apparentto one skilled in the art from consideration of the specification orpractice of the invention as disclosed herein. It is intended that thespecification, together with the examples, be considered to be exemplaryonly, with the scope and spirit of the invention being indicated by theclaims which follow the examples. In the examples, all percentages aregiven on a Weight basis unless otherwise indicated.

COMPARATIVE EXAMPLE 1

[1030] This example shows the preparation of celecoxib.

[1031] Step 1: Preparation of1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione.

[1032] Following the disclosure provided in U.S. Pat. No. 5,760,068,4′-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL ofmethanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol(25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours,the mixture was cooled to room temperature and concentrated. 100 mL 10%HCl was added and the mixture extracted with 4×75 mL ethyl acetate. Theextracts were dried over MgSO₄, filtered and concentrated to afford 8.47g (94%) of a brown oil which was carried on without furtherpurification.

[1033] Step 2: Preparation of4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

[1034] To the dione from Step 1 (4.14 g, 18.0 mmol) in 75 mL absoluteethanol, 4.26 g (19.0 mmol) 4-sulphonamidophenylhydrazine hydrochloridewas added. The reaction was refluxed under argon for 24 hours. Aftercooling to room temperature and filtering, the reaction mixture wasconcentrated to afford 6.13 g of an orange solid. The solid wasrecrystallized from methylene chloride/hexane to give 3.11 g (8.2 mmol,46%) of the product as a pale yellow solid, having a melting point (mp)of 157⁰-159° C.; and a calculated composition of C₁₇H₁₄N₃ 02 SF₃; C,53.54; H, 3.70; N, 11.02. The composition that was found by analysiswas: C, 53.17; H, 3.81; N, 10.90.

EXAMPLE 2

[1035] This illustrates the production of a composition containingcelecoxib and the combination of an antihistamine, a decongestant, anantitussive and an analgesic, and of a pharmaceutical compositioncontaining the combination.

[1036] The combination of an antihistamine, a decongestant, anantitussive and an analgesic may be supplied by any one of severalcommercially available preparations. One such preparation isALKA-SELTZER® PLUS LIQUI-GELS COLD & COUGH MEDICINE, available fromBayer Corporation, Elkhart, Ind. Each liqui-gel capsule of ALKA-SELTZER®PLUS LIQUI-GELS COLD & COUGH MEDICINE contains chlorpheniramine maleate,2 mg; pseudoephedrine hydrochloride, 30 mg; dextromethorphanhydrobromide, 10 mg; and acetaminophen, 325 mg.

[1037] Celecoxib can be prepared as described in Comparative Example 1,or it can be obtained under the trade name CELEBREX® from PharmaciaCorporation, Peapack, N.J.

[1038] A therapeutic composition of the present invention can be formedby intermixing chlorpheniramine maleate, 2 g; pseudoephedrinehydrochloride, 30 g; dextromethorphan hydrobromide, 10 g; acetaminophen,325 g, and4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(200 g, as produced in Comparative Example 1, or as available fromPharmacia Corporation, Peapack, N.J., under the tradename CELEBREX®), ina suspension or solution with a sterile pharmaceutically acceptableliquid. After mixing, the combination of chlorpheniramine maleate,pseudoephedrine hydrochloride, dextromethorphan hydrobromide,acetaminophen, and celecoxib forms a therapeutic composition that issufficient for the production of about 1000 human single dose units.Each single dose unit contains about 2 mg of chlorpheniramine maleate,30 mg of pseudoephedrine hydrochloride, 10 mg of dextromethorphanhydrobromide, 325 mg of acetaminophen and about 200 mg of celecoxib.

[1039] If desirable, a solid carrier and other materials may beintermixed with the therapeutic composition to form a pharmaceuticalcomposition and the resulting pharmaceutical composition may be formedinto capsules for human consumption, for example, by conventionalcapsule-forming equipment, where each capsule contains can contain aboutthe same amount of the active ingredients as each of the single doseunits of the liquid preparation described above.

[1040] Therapeutic and pharmaceutical compositions comprising acombination of any of the cyclooxygenase-2 selective inhibitors and anyof the sources of cold and cough active ingredients that are describedabove can be formed by similar methods.

EXAMPLE 3

[1041] This illustrates the production of a composition containingcelecoxib and aciclovir, and of a pharmaceutical composition containingthe combination.

[1042] Aciclovir (acyclovir) is available in the form of capsules,tablets and as a suspension under the trade name ZOVIRAX® fromGlaxoSmith Kline, Research Triangle Park, N.C. Celecoxib can be preparedas described in Comparative Example 1, or it can be obtained under thetrade name CELEBREX® from Pharmacia Corporation, Peapack, N.J.

[1043] A therapeutic composition of the present invention can be formedby intermixing solid or powdered aciclovir (400 g, available asZOVIRAX®, from GlaxoSmithKline), and4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(200 g, as produced in Comparative Example 1, or as available fromPharmacia Corporation, Peapack, N.J., under the tradename CELEBREX®), ina laboratory mill or mixing device suitable for intimate mixing ofpowders without substantial generation of shear or temperaturesufficient to degrade either of the two compounds. After mixing, thecombination of aciclovir and celecoxib forms a therapeutic compositionthat is sufficient for the production of about 1000 human single doseunits. Each single dose unit contains about 400 mg of aciclovir andabout 200 mg of celecoxib.

[1044] If desirable, a solid carrier and other materials may beintermixed with the therapeutic composition to form a pharmaceuticalcomposition and the resulting pharmaceutical composition may be formedinto capsules for human consumption, for example, by conventionalcapsule-forming equipment, where each capsule contains 400 mg ofaciclovir and 200 mg celecoxib.

[1045] Alternatively, the aciclovir (preferably in the form of asuspension) and the celecoxib may be dissolved or suspended into aliquid carrier, such as, for example, normal saline solution, to form apharmaceutical composition suitable for human consumption. A singledosage of the liquid pharmaceutical composition for human use would be avolume sufficient to provide 400 mg of aciclovir and 200 mg ofcelecoxib.

[1046] Therapeutic and pharmaceutical compositions comprising acombination of any of the cyclooxygenase-2 selective inhibitors and anyof the colds and cough active ingredients that are described above canbe formed by similar methods.

[1047] All references cited in this specification, including withoutlimitation all papers, publications, patents, patent applications,presentations, texts, reports, manuscripts, brochures, books, internetpostings, journal articles, periodicals, and the like, are herebyincorporated by reference into this specification in their entireties.The discussion of the references herein is intended merely to summarizethe assertions made by their authors and no admission is made that anyreference constitutes prior art. Applicants reserve the right tochallenge the accuracy and pertinency of the cited references.

[1048] In view of the above, it will be seen that the several advantagesof the invention are achieved and other advantageous results obtained.

[1049] As various changes could be made in the above methods andcompositions without departing from the scope of the invention, it isintended that all matter contained in the above description shall beinterpreted as illustrative and not in a limiting sense.

What is claimed is:
 1. A method for the treatment, prevention andamelioration of colds and/or cough in a subject in need of suchtreatment, prevention and amelioration, the method comprisingadministering to the subject a cyclooxygenase-2 selective inhibitor orprodrug thereof and one or more colds and cough active ingredient. 2.The method according to claim 1, except that when the colds and coughactive ingredient is an analgesic, it is free of the isolated salt formof acetaminophen.
 3. The method according to claim 1, wherein at least aportion of the colds and cough active ingredient is free of an isolatedmetal salt form of the colds and cough active ingredient.
 4. The methodaccording to claim 1, wherein the cyclooxygenase-2 selective inhibitorand a colds and cough active ingredient are administered to the subjectin combination and where the amount of the cyclooxygenase-2 selectiveinhibitor and the amount of the one or more colds and cough activeingredient together comprise an effective amount of the combination. 5.The method according to claim 4, wherein the effective amount of thecombination is a therapeutically effective amount for the treatment,prevention and/or amelioration of colds and cough in the subject.
 6. Themethod according to claim 1, wherein the colds and cough activeingredient comprises an antihistamine, antitussive, analgesic,expectorant, decongestant, anticholinergic, antiviral agent, or amixture of two or more thereof.
 7. The method according to claim 6,wherein the colds and cough active ingredient comprises anantihistamine.
 8. The method according to claim 7, wherein theantihistamine is selected from the group consisting of azatadine,bromodiphenhydramine, brompheniramine, brompheniramine maleate,carbinoxamine, chlorpheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, phenindamine, pheniramine, phenyltoloxamine, promethazine,pyrilamine, triprolidine, cetirzine, loratadine, and mixtures thereof.9. The method according to claim 6, wherein the colds and cough activeingredient comprises an antitussive.
 10. The method according to claim9, wherein the antitussive is selected from the group consisting ofcodeine, dihydrocodeine, hydrocodone, hydrocodone bitartrate,hydromorphone, carbetapentane, caraminphen, dextromethorphan,chlorphedianol, noscarpine, and mixtures thereof.
 11. The methodaccording to claim 6, wherein the colds and cough active ingredientcomprises an analgesic.
 12. The method according to claim 11, whereinthe analgesic is selected from the group consisting of acetaminophen,aspirin, salicylamide, sodium salicylate, indomethacin, ibuprofen,naproxen, flubiprofen, carprofen, tiaprofenic acid, cicloprofen,detoprofen, ketorolac, etodolac, and mixtures thereof.
 13. The methodaccording to claim 6, wherein the colds and cough active ingredientcomprises an expectorant.
 14. The method according to claim 13, whereinthe expectorant is selected from the group consisting of guaifenesin,glycerol guaiacolate, terpin hydrate, ammonium chloride,N-acetylesteine, bromhexine, ambroxol, domiodol, 3-iodo-1,2-propanediol,and mixtures thereof.
 15. The method according to claim 6, wherein thecolds and cough active ingredient comprises a decongestant.
 16. Themethod according to claim 15, wherein the decongestant is selected fromthe group consisting of ephedrine, ephinephrine, levodesoxyephedrine,oxymetazoline, naphazoline, phenylephrine, phenylpropanolamine,propylhexedrine, pseudoephedrine, xylometazoline, and mixtures thereof.17. The method according to claim 6, wherein the colds and cough activeingredient comprises an anticholinergic.
 18. The method according toclaim 17, wherein the anticholinergic comprises homatropine.
 19. Themethod according to claim 6, wherein the colds and cough activeingredient comprises an antiviral agent.
 20. The method according toclaim 19, wherein the antiviral agent is selected from the groupconsisting of dipyridamole, ICI 130,685, impulsin, pleconaril,zanamivir, oseltamivir, famciclovir, valaciclovir, valganciclovir,aciclovir, ganciclovir, idoxuridine, vidarabine, trifluridine,penciclovir, valacyclovir, foscarnet, ribavarin, amantadine,rimantadine, cidofovir, and mixtures of two or more of these compounds.21. The method according to claim 6, wherein the colds and cough activeingredient is selected from the group consisting of azatadine,bromodiphenhydramine, brompheniramine, brompheniramine maleate,carbinoxamine, chlorpheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, phenindamine, pheniramine, phenyltoloxamine, promethazine,pyrilamine, triprolidine, cetirzine, loratadine, codeine,dihydrocodeine, hydrocodone, hydrocodone bitartrate, hydromorphone,carbetapentane, caraminphen, dextromethorphan, acetaminophen, aspirin,salicylamide, sodium salicylate, guaifenesin, ephedrine, ephinephrine,levodesoxyephedrine, oxymetazoline, naphazoline, phenylephrine,phenylpropanolamine, propylhexedrine, pseudoephedrine, xylometazoline,homatropine, dipyridamole, ICI 130,685, impulsin, pleconaril, zanamivir,oseltamivir, famciclovir, valaciclovir, valganciclovir, aciclovir,ganciclovir, idoxuridine, vidarabine, trifluridine, penciclovir,valacyclovir, foscarnet, ribavarin, amantadine, rimantadine, cidofovir,and mixtures of two or more thereof.
 22. The method according to claim1, wherein the cyclooxygenase-2 selective inhibitor or prodrug thereofhas a cyclooxygenase-2 IC₅₀ of less than about 0.2 μmol/L.
 23. Themethod according to claim 22, wherein the cyclooxygenase-2 selectiveinhibitor or prodrug thereof has a cyclooxygenase-1 IC₅₀ of at leastabout 1 μmol/L.
 24. The method according to claim 23, wherein thecyclooxygenase-2 selective inhibitor or prodrug thereof has acyclooxygenase-1 IC₅₀ of at least about 10 μmol/L.
 25. The methodaccording to claim 1, wherein the cyclooxygenase-2 selective inhibitoris selected from the group consisting of celecoxib, valdecoxib,deracoxib, rofecoxib, etoricoxib, parecoxib, lumiracoxib, SD-8381,ABT-963, BMS-347070, and NS-398.
 26. The method according to claim 25,wherein the cycloxygenase-2 selective inhibitor comprises a compoundselected from the group consisting of celecoxib, valdecoxib andparecoxib.
 27. The method according to claim 6, wherein the one or morecolds and cough active ingredients comprise an antihistamine and anantitussive.
 28. The method according to claim 6, wherein the one ormore colds and cough active ingredient comprises an antihistamine, anantitussive, and an analgesic.
 29. The method according to claim 6,wherein the one or more colds and cough active ingredient comprises anantihistamine, an antitussive, and an expectorant.
 30. The methodaccording to claim 6, wherein the one or more colds and cough activeingredient comprises an antihistamine, a decongestant and anantitussive.
 31. The method according to claim 6, wherein the one ormore colds and cough active ingredient comprises an antihistamine, adecongestant, an antitussive and an analgesic.
 32. The method accordingto claim 6, wherein the one or more colds and cough active ingredientcomprises an antihistamine, a decongestant, an antitussive and anexpectorant.
 33. The method according to claim 6, wherein the one ormore colds and cough active ingredient comprises an antihistamine, adecongestant, an antitussive, an expectorant and an analgesic.
 34. Themethod according to claim 6, wherein the one or more colds and coughactive ingredient comprises an antihistamine, a decongestant and anexpectorant.
 35. The method according to claim 6, wherein the one ormore colds and cough active ingredient comprises an antihistamine, adecongestant, an expectorant and an analgesic.
 36. The method accordingto claim 6, wherein the one or more colds and cough active ingredientcomprises an antihistamine and an expectorant.
 37. The method accordingto claim 6, wherein the one or more colds and cough active ingredientcomprises an antitussive and an analgesic.
 38. The method according toclaim 6, wherein the one or more colds and cough active ingredientcomprises an antitussive and an antichlolinergic.
 39. The methodaccording to claim 6, wherein the one or more colds and cough activeingredient comprises an antitussive and an expectorant.
 40. The methodaccording to claim 6, wherein the one or more colds and cough activeingredient comprises a decongestant and an antitussive.
 41. The methodaccording to claim 6, wherein the one or more colds and cough activeingredient comprises a decongestant, an antitussive and an analgesic.42. The method according to claim 6, wherein the one or more colds andcough active ingredient comprises a decongestant, an antitussive and anexpectorant.
 43. The method according to claim 6, wherein the one ormore colds and cough active ingredient comprises a decongestant, anantitussive, an expectorant and an analgesic.
 44. The method accordingto claim 6, wherein the one or more colds and cough active ingredientcomprises a decongestant and an expectorant.
 45. The method according toclaim 6, wherein the colds and cough active ingredient comprises anantihistamine and a decongestant.
 46. A composition for the treatment,prevention and amelioration of colds and/or cough in a subject in needof such treatment, prevention and amelioration, the compositioncomprising a cyclooxygenase-2 selective inhibitor and a colds and coughactive ingredient.
 47. The composition according to claim 46, exceptthat when the colds and cough active ingredient is an analgesic, it isfree of the isolated salt form of acetaminophen.
 48. The compositionaccording to claim 46, wherein at least a portion of the colds and coughactive ingredient is free of an isolated metal salt form of the coldsand cough active ingredient.
 49. The composition according to claim 46,wherein the colds and cough active ingredient is selected from the groupconsisting of azatadine, bromodiphenhydramine, brompheniramine,brompheniramine maleate, carbinoxamine, chlorpheniramine,dexchlorpheniramine, diphenhydramine, doxylamine, phenindamine,pheniramine, phenyltoloxamine, promethazine, pyrilamine, triprolidine,cetirzine, loratadine, codeine, dihydrocodeine, hydrocodone, hydrocodonebitartrate, hydromorphone, carbetapentane, caraminphen,dextromethorphan, acetaminophen, aspirin, salicylamide, sodiumsalicylate, guaifenesin, ephedrine, ephinephrine, levodesoxyephedrine,oxymetazoline, naphazoline, phenylephrine, phenylpropanolamine,propylhexedrine, pseudoephedrine, xylometazoline, homatropine,dipyridamole, ICI 130,685, impulsin, pleconaril, zanamivir, oseltamivir,famciclovir, valaciclovir, valganciclovir, aciclovir, ganciclovir,idoxuridine, vidarabine, trifluridine, penciclovir, valacyclovir,foscarnet, ribavarin, amantadine, rimantadine, cidofovir, and mixturesof two or more thereof.
 50. The composition according to claim 46,wherein the cyclooxygenase-2 selective inhibitor is selected from thegroup consisting of celecoxib, valdecoxib, deracoxib, rofecoxib,etoricoxib, parecoxib, lumiracoxib, SD-8381, ABT-963, BMS-347070,NS-398, mixtures of any two or more thereof, and prodrugs thereof.
 51. Acomposition for the treatment, prevention and amelioration of coldsand/or cough in a subject in need of such treatment, prevention andamelioration, the composition comprising a cyclooxygenase-2 selectiveinhibitor selected from the group consisting of celecoxib, parecoxib andvaldecoxib, and a colds and cough active ingredient selected from thegroup consisting of chlorpheniramihe, cetirzine, loratadine, codeine,hydrocodone, carbetapentane, dextromethorphan, aspirin, guaifenesin,ephedrine, ephinephrine, phenylephrine, phenylpropanolamine,pseudoephedrine, impulsin, pleconaril, aciclovir, and ganciclovir.
 52. Acomposition for the treatment, prevention and amelioration of coldsand/or cough in a subject in need of such treatment, prevention andamelioration, the composition comprising a cyclooxygenase-2 selectiveinhibitor and a combination of two or more colds and cough activeingredients.
 53. The composition according to claim 52, wherein thecombination of two or more colds and cough active ingredients comprisesat least two agents selected from the group consisting of antihistamine,antitussive, analgesic, expectorant, decongestant, anticholinergic, andantiviral agent.
 54. The composition according to claim 53, wherein thecombination of two or more colds and cough active ingredients comprisesat least two agents selected from the group consisting of azatadine,bromodiphenhydramine, brompheniramine, brompheniramine maleate,carbinoxamine, chlorpheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, phenindamine, pheniramine, phenyltoloxamine, promethazine,pyrilamine, triprolidine, cetirzine, loratadine, codeine,dihydrocodeine, hydrocodone, hydrocodone bitartrate, hydromorphone,carbetapentane, caraminphen, dextromethorphan, aspirin, salicylamide,sodium salicylate, guaifenesin, ephedrine, ephinephrine,levodesoxyephedrine, oxymetazoline, naphazoline, phenylephrine,phenylpropanolamine, propylhexedrine, pseudoephedrine, xylometazoline,homatropine, dipyridamole, ICI 130,685, impulsin, pleconaril, zanamivir,oseltamivir, famciclovir, valaciclovir, valganciclovir, aciclovir,ganciclovir, idoxuridine, vidarabine, trifluridine, penciclovir,valacyclovir, foscarnet, ribavarin, amantadine, rimantadine, cidofovir,and mixtures of two or more thereof.
 55. The composition according toclaim 54, wherein the cyclooxygenase-2 selective inhibitor is selectedfrom the group consisting of celecoxib, valdecoxib, deracoxib,rofecoxib, etoricoxib, parecoxib, lumiracoxib, SD-8381, ABT-963,BMS-347070, NS-398, mixtures of any two or more thereof, and prodrugsthereof.
 56. A pharmaceutical composition for the treatment, preventionand amelioration of colds and/or cough in a subject in need of suchtreatment, prevention and amelioration, the composition comprising acyclooxygenase-2 selective inhibitor, a colds and cough activeingredient, and a pharmaceutically-acceptable excipient.
 57. A kit thatis suitable for use in the treatment, prevention or amelioration ofcolds and/or cough, the kit comprises a first dosage form comprising acolds and cough active ingredient and a second dosage form comprising acyclooxygenase-2 selective inhibitor or prodrug thereof, in quantitieswhich comprise a therapeutically effective amount of the combination ofthe compounds for the treatment, prevention, or amelioration of coldsand/or cough.